ORCID Profile
0000-0003-2101-8843
Current Organisations
The University of Newcastle
,
Imperial College London
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biochemistry and Cell Biology | Infectious Agents | Cellular immunology | Innate immunity | Immunology not elsewhere classified | Innate Immunity | Cellular Immunology | Respiratory Diseases | Receptors and Membrane Biology | Immunology | Cell Development, Proliferation and Death |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Immune System and Allergy | Infectious Diseases
Related Links
Publications
Developing a novel integrated model of p38 MAPK and glucocorticoid signalling pathways
Publisher: IEEE
Date: 05-2012
Oxidative stress modulates theophylline effects on steroid responsiveness
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.BBRC.2008.10.065
Abstract: Oxidative stress is a central factor in many chronic inflammatory diseases such as severe asthma and chronic obstructive pulmonary disease (COPD). Oxidative stress reduces the anti-inflammatory corticosteroid action and may therefore contribute to the relative corticosteroid insensitivity seen in these diseases. Low concentrations of theophylline can restore the anti-inflammatory action of corticosteroids in oxidant exposed cells, however the mechanism remains unknown. Here, we demonstrate that a low concentration of theophylline restores corticosteroid repression of pro-inflammatory mediator release and histone acetylation in oxidant exposed cells. Global gene expression analysis shows that theophylline regulates distinct pathways in naïve and oxidant exposed cells and reverses oxidant mediated modulated of pathways. Furthermore, quantitative chemoproteomics revealed that theophylline has few high affinity targets in naive cells but an elevated affinity in oxidant stressed cells. In conclusion, oxidative stress alters theophylline binding profile and gene expression which may result in restoration of corticosteroid function.
Kinase Targets and Inhibitors for the Treatment of Airway Inflammatory Diseases
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.2165/00063030-200418030-00003
Abstract: Kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function, and in airway remodeling. Important pro-inflammatory transcription factors such as activating protein-1 and nuclear factor kappaB, which are activated in airway disease, require kinase activation to switch on inflammatory genes, while other kinases can regulate mRNA half-life. Selective kinase inhibitors have been developed that reduce inflammatory gene expression and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or overactive in disease should allow for selective treatment of airway inflammatory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukemia viral oncogene homolog tyrosine kinase inhibitor, imatinib mesylate, in the treatment of chronic myelogenous leukemia. Encouraging data from animal models and primary cells and early phase I and II studies in other diseases suggest that inhibitors of p38 mitogen-activated protein kinase and inhibitor of kappaB kinase-2 may prove to be useful novel therapies in the treatment of severe asthma and chronic obstructive pulmonary disease.
A bioinformatics analysis of exosomal microRNAs released following mycobacterial infection
Publisher: Medknow
Date: 2019
Abstract: Tuberculosis (TB) still remains a major health threat worldwide. The current TB diagnostics are suboptimal, and there is a high clinical need for identifying novel biomarkers of disease prevalence. Circulating exosomes have been currently attractive as novel biomarkers in a wide range of pathological conditions. In this study, we performed bioinformatics analysis on the downstream targets of a dysregulated microRNA (miRNA) cluster induced by Bacillus Calmette-Guerin infection of human macrophages to provide greater understanding of their potential roles in disease pathogenesis. Our analysis demonstrated that these dysregulated miRNAs have central roles in the host metabolic and energy pathways. This suggests that the host miRNA network is perturbed by Mycobacterium to re-patterning host metabolism machinery to favor its intracellular survival. The dysregulated miRNAs can be delivered to local and distal cells by exosomes and thereby modulate their function.
Differential Regulation and Function of 5′-Untranslated GR-Exon 1 Transcripts
Publisher: The Endocrine Society
Date: 07-2011
DOI: 10.1210/ME.2010-0436
Epigenetics of asthma
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.BBAGEN.2011.03.006
Abstract: Asthma is caused by both heritable and environmental factors. It has become clear that genetic studies do not adequately explain the heritability and susceptibility to asthma. The study of epigenetics, heritable non-coding changes to DNA may help to explain the heritable component of asthma. Additionally, epigenetic modifications can be influenced by the environment, including pollution and cigarette smoking, which are known asthma risk factors. These environmental trigger-induced epigenetic changes may be involved in skewing the immune system towards a Th2 phenotype following in utero exposure and thereby enhancing the risk of asthma. Alternatively, they may directly or indirectly modulate the immune and inflammatory processes in asthmatics via effects on treatment responsiveness. The study of epigenetics may therefore play an important role in our understanding and possible treatment of asthma and other allergic diseases. This article is part of a Special Issue entitled: Biochemistry of Asthma.
Update on CADSET (Chronic Airway Disease Early Stratification) Clinical Research Collaboration
Publisher: European Respiratory Society
Date: 07-09-2020
Exosomal miRNAs and association with pulmonary tuberculosis
Publisher: European Respiratory Society
Date: 28-09-2019
High-Throughput Sequencing in Respiratory, Critical Care, and Sleep Medicine Research. An Official American Thoracic Society Workshop Report
Publisher: American Thoracic Society
Date: 2019
The Potential Biomarkers and Immunological Effects of Tumor-Derived Exosomes in Lung Cancer
Publisher: Frontiers Media SA
Date: 18-04-2018
Systems medicine and integrated care to combat chronic noncommunicable diseases
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/GM259
Cigarette Smoke Activates Human Monocytes by an Oxidant-AP-1 Signaling Pathway: Implications for Steroid Resistance
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 08-2005
Abstract: Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smoking-induced pathophysiology is often resistant to the anti-inflammatory effects of glucocorticoids. The nature of cigarette smoke-induced inflammation is still not defined, although neutrophil recruitment and activation seem to be consistent features. In the current study, we have used a range of approaches to demonstrate that cigarette smoke activates human monocytes and macrophages to release the CXC chemokine CXCL8 [(interleukin-8 (IL-8)]. Furthermore, we show for the first time that cigarette smoke synergizes with proinflammatory cytokines IL-1beta and tumor necrosis factor-alpha, and it is this interaction that confers steroid resistance to smoke-induced CXCL8 release. We go on to show that smoke-induced activation of human cells is an oxidant-mediated phenomenon acting through activator protein-1, but not nuclear factor kappaB, pathway. These observations add significantly to our understanding of smoke as an inflammatory stimulus that has implications for potential the development of treatments of smoking or related disease.
Asthma similarities across ProAR (Brazil) and U-BIOPRED (Europe) adult cohorts of contrasting locations, ethnicity and socioeconomic status
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.RMED.2019.105817
Abstract: Asthma prevalence is 339 million globally. 'Severe asthma' (SA) comprises subjects with uncontrolled asthma despite proper management. To compare asthma from erse ethnicities and environments. A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED. Among SA subjects, age, weight, proportion of former smokers and FEV ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.
MicroRNA Expression Profiling in Mild Asthmatic Human Airways and Effect of Corticosteroid Therapy
Publisher: Public Library of Science (PLoS)
Date: 12-06-2009
New understanding in the treatment of cough (NEUROCOUGH) ERS Clinical Research Collaboration: improving care and treatment for patients with cough
Publisher: European Respiratory Society (ERS)
Date: 05-2019
Albuterol Does Not Antagonize the Inhibitory Effect of Dexamethasone on Monocyte Cytokine Release
Publisher: American Thoracic Society
Date: 03-1998
DOI: 10.1164/AJRCCM.157.3.9707116
Abstract: Beta2-adrenoceptor agonists given by the inhaled route are the most effective bronchodilators known, yet high doses of these drugs may be associated with an increase in asthma mortality and morbidity. One theory for this paradox is that chronic use of beta2-adrenoceptor agonists compromises the anti-inflammatory action of glucocorticosteroids. This hypothesis derives from the ability of albuterol and fenoterol to inhibit the interaction of the glucocorticosteroid receptor (GR) with proinflammatory transcriptional activators acting on the promoter region of certain target genes that encode cytokines such as tumor necrosis factor-alpha (TNF alpha) and granulocyte/macrophage colony-stimulating factor (GM-CSF). However, the functional relevance of these results has not been formally investigated. We have tested the hypothesis that albuterol reduces the ability of dexamethasone to inhibit the generation of TNF alpha and GM-CSF from lipopolysaccharide (LPS)-stimulated human monocytes. Pretreatment of human monocytes with albuterol (1 and 100 microM) for 5 and for 180 min inhibited maximally TNF alpha generation by approximately 25%. However, regardless of the concentration of albuterol, or the time of preincubation, the inhibitory effect of dexamethasone was not significantly affected with respect to the EC50 or the maximal effect produced. Qualitatively identical data were obtained when GM-CSF release was used as an index of monocyte activation. We conclude that high concentrations of albuterol do not compromise the ability of dexamethasone to suppress the generation of TNF alpha and GM-CSF from LPS-stimulated human monocytes.
Exhaled nitric oxide is not a biomarker for idiopathic pulmonary arterial hypertension or for treatment efficacy
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1186/S12890-019-0954-Z
Abstract: Idiopathic pulmonary arterial hypertension (IPAH) is a fatal illness. Despite many improvements in the treatment of these patients, there is no unique prognostic variable available to track these patients. The aim of this study was to evaluate the association between fractional exhaled nitric oxide (FeNO) levels, as a noninvasive biomarker, with disease severity and treatment outcome. Thirty-six patients (29 women and 7 men, mean age 38.4 ± 11.3 years) with IPAH referred to the outpatient’s clinic of Masih Daneshvari Hospital, Tehran, Iran, were enrolled into this pilot observational study. Echocardiography, six-minute walking test (6MWT), FeNO, brain natriuretic peptide (BNP) levels and the functional class of patients was assessed before patients started treatment. Assessments were repeated after three months. 30 healthy non-IPAH subjects were recruited as control subjects. There was no significant difference in FeNO levels at baseline between patients with IPAH and subjects in the control group. There was also no significant increase in FeNO levels during the three months of treatment and levels did not correlate with other disease measures. In contrast, other markers of disease severity were correlated with treatment effect over the three months. FeNO levels are a poor non-invasive measure of IPAH severity and of treatment response in patients in this pilot study.
The “Iron”-y of Iron Overload and Iron Deficiency in Chronic Obstructive Pulmonary Disease
Publisher: American Thoracic Society
Date: 11-2017
Inflammatory Mechanisms in Asthma
Publisher: Elsevier
Date: 2022
Steroid Responsiveness of Renal Epithelial Cells
Publisher: Elsevier BV
Date: 02-2003
Oxidative/nitrosative stress selectively altered A2Badenosine receptors in chronic obstructive pulmonary disease
Publisher: Wiley
Date: 14-10-2009
DOI: 10.1096/FJ.09-139485
Abstract: The primary aim of this study was to investigate adenosine receptors (ARs) in bronchoalveolar lavage (BAL) macrophages from patients with chronic obstructive pulmonary disease (COPD) and age-matched healthy smokers. A(2B)ARs were significantly decreased in BAL macrophages from patients with COPD when compared with healthy smokers. The effect of proinflammatory cytokines and oxidative/nitrosative stress on AR expression and function in U937 cells before and after PMA treatment was evaluated. IL-1beta and TNF-alpha treatment up-regulated A(2A)- and A(3)ARs but not A(1)- or A(2B)ARs, whereas IL-6 did not modify AR expression. In contrast, oxidative/nitrosative stress selectively decreased A(2B)AR expression, which was associated with a reduction in the potency of the adenosine agonist 5'-N-ethylcarboxamideadenosine (NECA) to induce cAMP. Further, the ability of NECA to enhance cell proliferation was increased after oxidative/nitrosative stress. The specific involvement of A(2B)ARs was investigated by using potent and selective A(2B)AR antagonist and by A(2B)AR knockdown using siRNA and demonstrated responses similar to those obtained with oxidative/nitrosative stress. N-acetylcysteine (NAC), an antioxidant agent, counteracted the decrease in A(2B)AR expression, as well as the altered NECA effects on cAMP and cell proliferation. These findings highlight the central role of A(2B)ARs in alveolar macrophages, suggesting that their modulation could represent an innovative pharmacological strategy to manage COPD.-Varani, K., Caramori, G., Vincenzi, F., Tosi, A., Barczyk, A., Contoli, M., Casolari, P., Triggiani, M., Hansel, T., Leung, E., MacLennan, S., Barnes, P. J., Fan Chung, K., Adcock, I., Papi, A., Borea, P. A. Oxidative/nitrosative stress selectively altered A(2B) adenosine receptors in chronic obstructive pulmonary disease.
Increased neutrophil gelatinase-associated lipocalin (NGAL) promotes airway remodelling in chronic obstructive pulmonary disease
Publisher: Portland Press Ltd.
Date: 22-05-2017
DOI: 10.1042/CS20170096
Abstract: Airway remodelling is an important component of chronic obstructive pulmonary disease (COPD). Neutrophil gelatinase-associated lipocalin (NGAL) from neutrophils may drive COPD epithelial–mesenchymal transition (EMT). NGAL expression was quantified in the lungs of COPD patients and bronchoalveolar lavage fluid (BALF) of ozone-treated mice. Reticular basement membrane (RBM) thickness and E-cadherin and α-smooth muscle actin (α-SMA) expression were determined in mice airways. Effects of cigarette smoke extract (CSE) and inflammatory factors on NGAL expression in human neutrophils as well as the effects of NGAL on airway structural cells was assessed. NGAL was mainly distributed in neutrophils and enhanced in lung tissues of both COPD patients and BALF of ozone-treated mice. We showed decreased E-cadherin and increased α-SMA expression in bronchial epithelium and increased RBM thickness in ozone-treated animals. In vitro, CSE, IL-1β and IL-17 enhanced NGAL mRNA expression in human neutrophils. NGAL, in turn, down-regulated the expression of E-cadherin and up-regulated α-SMA expression in 16HBE cells via the WNT/glycogensynthase kinase-3β (GSK-3β) pathway. Furthermore, NGAL promoted the proliferation and migration of human bronchial smooth muscle cells (HASMCs). The present study suggests that elevated NGAL promotes COPD airway remodelling possibly through altered EMT. NGAL may be a potential target for reversing airway obstruction and remodelling in COPD.
Increased METEORIN-LIKE (ML) expression promotes lung inflammation in asthma
Publisher: European Respiratory Society
Date: 28-09-2019
Treatment Effects of Low-Dose Theophylline Combined With an Inhaled Corticosteroid in COPD
Publisher: Elsevier BV
Date: 06-2010
Abstract: Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD. To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 microg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L). In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV(1)% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD. Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD. clinicaltrials.gov Identifier NCT00241631.
Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy
Publisher: Informa Healthcare
Date: 15-05-2007
DOI: 10.1517/14728222.11.6.745
Abstract: Insensitivity to corticosteroid treatment in inflammatory conditions, such as asthma and chronic obstructive pulmonary disease, present considerable management problems and cost burdens to health services. Oxidative stress is a major component of chronic inflammation and can have a significant suppressive effect on corticosteroid efficacy. Recent advances in the understanding of both the mechanisms of corticosteroid action and corticosteroid insensitivity have provided hope for a therapeutic strategy of restoring corticosteroid sensitivity. Histone deacetylase 2 (HDAC-2) plays a pivotal role in corticosteroid action and is reduced in many cases of steroid insensitivity. Moreover, it has shown that oxidative stress can be responsible for this reduction in HDAC-2 activity. Two structurally different compounds methyl-xanthine theophylline and polyphenol curcumin restore HDAC activity, thereby restoring corticosteroid function. Low, subbronchodilator doses of theophylline can also act as corticosteroid-sparing drugs in asthmatics. Although these compounds appear to restore corticosteroid function and may initially provide therapeutic potential, they lack specificity and the mechanism of their action is unknown. Once their mechanisms of action are established, it is likely that derivatives of these compounds may be used as a therapeutic strategy to restore corticosteroid insensitivity in the future.
Regulation of Wnt4 in chronic obstructive pulmonary disease
Publisher: Wiley
Date: 05-03-2013
DOI: 10.1096/FJ.12-217083
NF-kB: a pivotal role in asthma and a new target for therapy
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1016/S0165-6147(97)89796-9
Abstract: Preoperative optimization programs have demonstrated positive effects on perioperative physical function and surgical outcomes. In nonsurgical populations, physical activity and healthy diet may reduce pain and pain medication requirement, but this has not been studied in surgical patients. Our aim was to determine whether a preoperative diet and exercise intervention affects postoperative pain and pain medication use. Patients undergoing abdominal colorectal surgery were invited to participate in a web-based patient engagement program. Those enrolling in the first and third time periods received information on the standard perioperative pathway (enhanced recovery after surgery [ERAS]). Those enrolling in the second time period also received reminders on nutrition and exercise (PREHAB + ERAS). The primary outcome was postoperative inpatient opioid use. The secondary outcomes were inpatient postoperative pain scores and nonopioid pain medication use. The ERAS and PREHAB + ERAS groups were similar in demographic and operative characteristics. Subgroup analysis of patients who activated their accounts demonstrated that the two groups had similar average maximum daily pain scores, but the PREHAB + ERAS group (n = 158) used 15.9 fewer oral morphine equivalents per postoperative inpatient day than the ERAS group (n = 92), representing a 30% decrease (53 mg versus 37.1 mg, P = 0.04). The two groups used comparable amounts of acetaminophen, gabapentin, and ketorolac. Generalized linear models demonstrated that PREHAB + ERAS, minimally invasive surgery, and older age were associated with lower inpatient opioid use. Access to a web-based preoperative diet and exercise program may reduce inpatient opioid use after major elective colorectal surgery. Further studies are necessary to determine whether the degree of adherence to nutrition and physical activity recommendations has a dose-dependent effect on opioid use.
Simvastatin Suppresses Airway IL-17 and Upregulates IL-10 in Patients With Stable COPD
Publisher: Elsevier BV
Date: 11-2015
A role for phosphoinositol 3–kinase δ in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.JACI.2010.02.003
Abstract: Glucocorticoid function is markedly impaired in the lungs of patients with chronic obstructive pulmonary disease (COPD). This reduction in glucocorticoid sensitivity might be due to an oxidant-mediated increase in phosphoinositol 3-kinase (PI3K) delta signaling. We sought to determine the role of PI3Kdelta in the reduced glucocorticoid responsiveness in patients with COPD. Peripheral lung tissue was obtained from 24 patients with COPD, 20 age-matched smokers with normal lung function, and 13 nonsmokers. Peripheral blood monocytes were isolated from 9 patients with COPD and 7 age-matched smokers with normal lung function and from healthy volunteers. The expressions of PI3Kdelta and Akt phosphorylation were increased in macrophages from patients with COPD compared with those from control groups of age-matched smokers and nonsmokers. In vitro oxidative stress induced phosphorylation of Akt in monocytes and macrophages, which was abolished by means of selective inhibition of PI3Kdelta but not PI3Kgamma. Dexamethasone was less effective at repressing LPS-induced GM-CSF and CXC motif chemokine 8 release in blood monocytes from patients with COPD compared with age-matched smokers. This reduced sensitivity was reversed by inhibition of PI3Kdelta but not PI3Kgamma. PI3Kdelta expression and signaling is increased in the lungs of patients with COPD. Selective inhibition of PI3Kdelta might restore glucocorticoid function in patients with COPD and might therefore present a potential therapeutic target.
Elevated serum polyclonal immunoglobulin free light chains in patients with severe asthma
Publisher: Frontiers Media SA
Date: 16-06-2023
DOI: 10.3389/FPHAR.2023.1126535
Abstract: Background: Inflammation plays a pivotal role in the pathophysiology of asthma. Free light chains (FLC) can cause inflammation by mast cell antigen-activation. Serum immunoglobulin (Ig) FLC κ, but not λ, were shown elevated in adult males with asthma. We sought to investigate if serum Ig FLC concentrations are affected by asthma severity and their relationships with inflammatory outcomes. Methods: By using immunoassays, we measured serum κ and λ Ig FLCs in 24 severe persistent asthma patients, 15 patients with moderate persistent asthma, 15 steroid-naïve mild persistent asthma patients and 20 healthy control subjects in a cross-sectional observational study. Total and specific serum IgE concentrations, fractional exhaled nitric oxide (F E NO), lung function, peripheral blood eosinophils and neutrophils, and C reactive protein (CRP) were also measured. Results: Serum κ FLC concentrations were elevated in severe asthma patients compared mild asthma patients ( p & 0.05) and healthy subjects ( p & 0.05). Serum λ FLCs were higher in severe asthma patients than in healthy subjects ( p & 0.05) and correlated with blood eosinophil counts (percentage, κ: r = 0.51, p = 2.9678 −6 λ: r = 0.42, p = 1.7377 −4 absolute values, κ: r = 0.45, p = 6.1284 −5 λ: r = 0.38, p = 7.8261 −4 ), but not with total or specific serum IgE. In severe asthma patients, serum Ig FLC correlated with serum CRP (κ: r = 0.33 p = 0.003 λ: r = 0.38, p = 8.8305 −4 ) and blood neutrophil cell counts (percentage, κ: r = 0.31 p = 0.008 λ: r = 0.29, p = 0.01 absolute values, κ: r = 0.40 p = 3.9176 −4 λ: r = 0.40, p = 4.5479 −4 ), were elevated in subjects with blood eosinophilia (≥300 cells/µL) ( n = 13) compared with non-eosinophilic subjects ( n = 10) (κ: 19.2 ± 1.2 mg/L versus 12.1 ± 1.3 mg/L, p & 0.001 λ: 27.2 ± 2.6 mg/L versus 16.8 ± 2.5 mg/L, p & 0.01), but were similar in atopic ( n = 15) versus nonatopic subjects ( n = 9) (κ: p = 0.20 λ: p = 0.80). Serum FLC were negatively correlated with lung function tests, including forced expiratory volume in one second (FEV1) (κ: r = −0.33 p = 0.0034 λ: r = −0.33 p = 0.0035), and FEV 1 /forced vital capacity ratio (κ: r = −0.33 p = 0.0034 λ: r = −0.33 p = 0.0036). Conclusion: Serum Ig FLCs are elevated in severe asthma adults and might represent new surrogate markers of inflammation. The pathophysiological implications of these findings require further research. This study was approved by the ethics committee of the University Hospital Agostino Gemelli Foundation and Catholic University of the Sacred Heart (approval number P/1034/CE2012).
The discovAIR project: a roadmap towards the Human Lung Cell Atlas
Publisher: European Respiratory Society (ERS)
Date: 27-01-2022
DOI: 10.1183/13993003.02057-2021
Abstract: The Human Cell Atlas (HCA) consortium aims to establish an atlas of all organs in the healthy human body at single-cell resolution to increase our understanding of basic biological processes that govern development, physiology and anatomy, and to accelerate diagnosis and treatment of disease. The Lung Biological Network of the HCA aims to generate the Human Lung Cell Atlas as a reference for the cellular repertoire, molecular cell states and phenotypes, and cell–cell interactions that characterise normal lung homeostasis in healthy lung tissue. Such a reference atlas of the healthy human lung will facilitate mapping the changes in the cellular landscape in disease. The discovAIR project is one of six pilot actions for the HCA funded by the European Commission in the context of the H2020 framework programme. discovAIR aims to establish the first draft of an integrated Human Lung Cell Atlas, combining single-cell transcriptional and epigenetic profiling with spatially resolving techniques on matched tissue s les, as well as including a number of chronic and infectious diseases of the lung. The integrated Human Lung Cell Atlas will be available as a resource for the wider respiratory community, including basic and translational scientists, clinical medicine, and the private sector, as well as for patients with lung disease and the interested lay public. We anticipate that the Human Lung Cell Atlas will be the founding stone for a more detailed understanding of the pathogenesis of lung diseases, guiding the design of novel diagnostics and preventive or curative interventions.
The Transcriptional Co-activators CREB-binding Protein (CBP) and p300 Play a Critical Role in Cardiac Hypertrophy That Is Dependent on Their Histone Acetyltransferase Activity
Publisher: Elsevier BV
Date: 02-2003
Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury
Publisher: Portland Press Ltd.
Date: 18-09-2015
DOI: 10.1042/CS20150273
Abstract: COPD (chronic obstructive pulmonary disease) is associated with sustained inflammation, excessive injury, and accelerated lung aging. Human Klotho (KL) is an anti-aging protein that protects cells against inflammation and damage. In the present study, we quantified KL expression in the lungs of COPD patients and in an ozone-induced mouse model of COPD, and investigated the mechanisms that control KL expression and function in the airways. KL distribution and levels in human and mouse airways were measured by immunohistochemistry and Western blotting. The effect of CSE (cigarette smoke extract) on KL expression was detected in human bronchial epithelial cells. Moreover, the effect of KL on CSE-mediated inflammation and hydrogen peroxide-induced cellular injury/apoptosis was determined using siRNAs. KL expression was decreased in the lungs of smokers and further reduced in patients with COPD. Similarly, 6 weeks of exposure to ozone decreased KL levels in airway epithelial cells. CSE and TNFα (tumour necrosis factor α) decreased KL expression and release from airway epithelial cells, which was associated with enhanced pro-inflammatory cytokine expression. Moreover, KL depletion increased cell sensitivity to cigarette smoke-induced inflammation and oxidative stress-induced cell damage. These effects involved the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and Nrf2 (nuclear factor erythroid 2-related factor 2) pathways. Reduced KL expression in COPD airway epithelial cells was associated with increased oxidative stress, inflammation and apoptosis. These data provide new insights into the mechanisms associated with the accelerated lung aging in COPD development.
Increased tachykinin receptor gene expression in asthmatic lung and its modulation by steroids
Publisher: Bioscientifica
Date: 08-1993
Abstract: Substance P has several inflammatory effects on the airways mediated via neurokinin 1 receptors (NK 1 Rs) and, if released from sensory nerves, may lify the chronic inflammation seen in asthma. Northern blot analysis of NK 1 R mRNA in lung showed a 52 ± 10% ( s.e.m. P ·01) increase in mRNA in the asthmatic lung compared with non-asthmatic control tissue. NK 1 R mRNA was reduced by 84·5 ± 1·9% after incubation with dexamethasone (1 μ m ) for 3 h ( P ·01). In contrast, NK 2 R mRNA was unaltered in asthmatic lungs and dexamethasone treatment had no effect on the level of NK 2 R mRNA. These results suggest that chronic inflammation in asthma may result in increased NK 1 R gene expression and that this effect is reversed by glucocorticosteroids.
The effects of glucocorticoids on phorbol ester and cytokine stimulated transcription factor activation in human lung
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0024-3205(94)00243-6
Abstract: Glucocorticoids have a wide variety of effects which result in the d ening of inflammatory and immune responses and other challenges to homeostasis. An important site of steroid action may be on the control of transcription factor binding to DNA. The interaction of the transcription factors, activator protein 1 (AP-1) and nuclear factor kappa from B cells (NF kappa B) with DNA and glucocorticoid receptors was analysed by gel mobility shift assays following stimulation by tumour necrosis factor alpha (TNF alpha) and a phorbol ester (PMA) that activates protein kinase C. PMA and TNF alpha both caused significant (180-340%) increases in AP-1 and NF kappa B DNA binding which peaked at 15 minutes and decreased to a constant elevated level at between 1-3 hrs and was sustained for 24hrs. Dexamethasone (1 microM) caused a rapid and long lasting 40-50% decrease in both AP-1 and NF kappa B DNA binding lasting over 24hrs. Combined treatment with dexamethasone and PMA or TNF alpha prevented the increase in both AP-1 and NF kappa B binding due to PMA and TNF alpha returning levels to those seen in control untreated s les. This suggests that in human lung, the glucocorticoid receptor functionally interacts within the nucleus with other transcription factors that are induced by inflammatory mediators such as cytokines. This may be an important molecular site of steroid action in chronic inflammatory lung diseases such as asthma.
ATP and the pathogenesis of COPD
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.EJPHAR.2010.04.019
Abstract: Extracellular ATP is a signalling molecule that often serves as a danger signal to alert the immune system of tissue damage. This molecule activates P2 nucleotide receptors, that include the ionotropic P2X receptors and the metabotropic P2Y receptors. Several publications highlight the importance of purinergic signalling in the pathogenesis of chronic airway inflammation. Recently, it has been reported that ATP accumulates in the airways of both animal models and patients with asthma or chronic obstructive pulmonary diseases (COPD) however, the role and function of ATP in the diseases process of COPD are not well understood. In this perspective, a brief overview is given on the role of ATP and P2 receptors in the pathogenesis of lung emphysema and COPD with a focus on neutrophils as messengers in intercellular communication between epithelial cells and macrophages and the activation of inflammasome pathways. Finding the link between purinergic signalling with inflammasome pathways will be a challenge for the future and could lead to the discovery of new therapeutic drugs for suppressing inflammation in the lungs of COPD patients.
Exosomes in Severe Asthma: Update in Their Roles and Potential in Therapy
Publisher: Hindawi Limited
Date: 2018
DOI: 10.1155/2018/2862187
Abstract: Exosomes are nanosized vesicles and have recently been recognized as important players in cell-to-cell communication. Exosomes contain different mediators such as proteins, nucleic acids (DNA, mRNA, miRNAs, and other ncRNAs), and lipid mediators and can shuttle their exosomal content to both neighboring and distal cells. Exosomes are very effective in orchestrating immune responses in the airways and all cell types can contribute to the systemic exosome pool. Intracellular communication between the broad range of cell types within the lung is crucial in disease emphasizing the importance of exosomes. In asthma, exosomes affect the inflammatory microenvironment which ultimately determines the development or alleviation of the pathological symptoms. Recent studies in this area have provided insight into the underlying mechanisms of disease and led to interest in using exosomes as potential novel therapeutic agents.
Effects of cigarette smoke extract on human airway smooth muscle cells in COPD
Publisher: European Respiratory Society (ERS)
Date: 25-06-2014
DOI: 10.1183/09031936.00171313
Abstract: We hypothesised that the response to cigarette smoke in airway smooth muscle (ASM) cells from smokers with chronic obstructive pulmonary disease (COPD) would be intrinsically different from smokers without COPD, producing greater pro-inflammatory mediators and factors relating to airway remodelling. ASM cells were obtained from smokers with or without COPD, and then stimulated with cigarette smoke extract (CSE) or transforming growth factor-β1. The production of chemokines and matrix metalloproteinases (MMPs) were measured by ELISA, and the deposition of collagens by extracellular matrix ELISA. The effects of CSE on cell attachment and wound healing were measured by toluidine blue attachment and cell tracker green wound healing assays. CSE increased the release of CXCL8 and CXCL1 from human ASM cells, and cells from smokers with COPD produced more CSE-induced CXCL1. The production of MMP-1, -3 and -10, and the deposition of collagen VIII alpha 1 (COL8A1) were increased by CSE, especially in the COPD group which had higher production of MMP-1 and deposition of COL8A1. CSE decreased ASM cell attachment and wound healing in the COPD group only. ASM cells from smokers with COPD were more sensitive to CSE stimulation, which may explain, in part, why some smokers develop COPD.
Differential responses of pulmonary vascular cells from PAH patients and controls to TNFα and the effect of the BET inhibitor JQ1
Publisher: Springer Science and Business Media LLC
Date: 29-07-2023
DOI: 10.1186/S12931-023-02499-Y
Abstract: Pulmonary arterial hypertension (PAH) encompasses a group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling and inflammation. Bromodomain and extra-terminal (BET) proteins are required for the expression of a subset of NF-κB-induced inflammatory genes which can be inhibited by the BET mimic JQ1+. We hypothesised that JQ+ would supress TNFα-driven inflammatory responses in human pulmonary vascular cells from PAH patients. Immunohistochemical staining of human peripheral lung tissue (N = 14 PAH and N = 12 non-PAH) was performed for the BET proteins BRD2 and 4 . Human pulmonary microvascular endothelial cells (HPMEC) and pulmonary artery smooth muscle cells (HPASMC) from PAH patients (N = 4) and non-PAH controls (N = 4) were stimulated with TNFα in presence or absence of JQ1+ or its inactive isomer JQ1–. IL-6 and -8 mRNA was measured by RT-qPCR and protein levels by ELISA. Chromatin immunoprecipitation analysis was performed using EZ-ChIP™ and NF-κB p65 activation determined using a TransAm kit. MTT assay was used to measure cell viability. Nuclear staining of BRD2 and BRD4 was significantly (p 0.0001) increased in the lung vascular endothelial and smooth muscle cells from PAH patients compared to controls with normal lung function. TNFα-driven IL-6 release from both HPMECs and HPASMCs was greater in PAH cells than control cells. Levels of CXCL8/IL-8 protein release was higher in PAH HPASMCs than in control cells with similar release observed in HPMECs. TNFα-induced recruitment of activated NF-κB p65 to the IL-6 and CXCL8/IL-8 promoters were similar in both cell types and between subject groups. JQ1+ suppressed TNFα-induced IL-6 and CXCL8/IL-8 release and mRNA expression to a comparable extent in control and PAH HPMECs and HPASMCs. JQ1 had a greater efficacy on IL-6 release in HPMEC and on CXCL8/IL-8 release in HPASMC. BET inhibition decreases TNFα driven inflammation in primary pulmonary vascular cells. The anti-inflammatory actions of JQ1 suggests distinct cell-specific regulatory control of these genes. BET proteins could be a target for future therapies for PAH.
S142 The role of H3K27 methylation in vascular endothelial cell proliferation and function: implications for pulmonary arterial hypertension
Publisher: BMJ
Date: 14-11-2013
A CADSET WP4 transcriptomic analysis of Asthma and COPD overlap
Publisher: European Respiratory Society
Date: 07-09-2020
IL1RAP expression and the enrichment of IL ‐33 activation signatures in severe neutrophilic asthma
Publisher: Wiley
Date: 28-08-2022
DOI: 10.1111/ALL.15487
Abstract: Interleukin (IL)‐33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes. To derive gene signatures from in vitro studies of IL‐33‐stimulated cells and use these to determine IL‐33‐associated enrichment patterns in asthma. Signatures downstream of IL‐33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U‐BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes. IL‐33‐activated gene signatures were cell‐specific with little gene overlap. In idual signatures, however, were associated with similar signalling pathways (TNF, NF‐κB, IL‐17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL‐33‐activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL‐33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL‐33 receptor, was up‐regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co‐receptor, was greatest in severe neutrophilic and mixed granulocytic asthma. IL‐33‐activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co‐receptor expression. This suggests incorporating T2‐low asthma in anti‐IL‐33 trials.
Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.BBRC.2014.06.111
Abstract: Idiopathic pulmonary arterial hypertension (IPAH) is an incurable condition leading to right ventricular failure and death and inflammation is postulated to be associated with vascular remodelling. Interleukin (IL)-33, a member of the "alarmin" family can either act on the membrane ST2 receptor or as a nuclear repressor, to regulate inflammation. We show, using immunohistochemistry, that IL-33 expression is nuclear in the vessels of healthy subjects whereas nuclear IL-33 is markedly diminished in the vessels of IPAH patients. This correlates with reduced IL-33 mRNA expression in their lung. In contrast, serum levels of IL-33 are unchanged in IPAH. However, the expression of the soluble form of ST2, sST2, is enhanced in the serum of IPAH patients. Knock-down of IL-33 in human endothelial cells (ECs) using siRNA is associated with selective modulation of inflammatory genes involved in vascular remodelling including IL-6. Additionally, IL-33 knock-down significantly increased sST2 release from ECs. Chromatin immunoprecipitation demonstrated that IL-33 bound multiple putative homeodomain protein binding motifs in the proximal and distal promoters of ST2 genes. IL-33 formed a complex with the histone methyltransferase SUV39H1, a transcriptional repressor. In conclusion, IL-33 regulates the expression of IL-6 and sST2, an endogenous IL-33 inhibitor, in primary human ECs and may play an important role in the pathogenesis of PAH through recruitment of transcriptional repressor proteins.
A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised t
Publisher: Springer Science and Business Media LLC
Date: 04-01-2018
Glucocorticoids
Publisher: Springer International Publishing
Date: 2016
DOI: 10.1007/164_2016_98
Abstract: The most effective anti-inflammatory drugs used to treat patients with airways disease are topical glucocorticosteroids (GCs). These act on virtually all cells within the airway to suppress airway inflammation or prevent the recruitment of inflammatory cells into the airway. They also have profound effects on airway structural cells to reverse the effects of disease on their function. Glucorticosteroids act via specific receptors-the glucocorticosteroid receptor (GR)-which are a member of the nuclear receptor family. As such, many of the important actions of GCs are to modulate gene transcription through a number of distinct and complementary mechanisms. Targets genes include most inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. GCs delivered by the inhaled route are very effective for most patients and have few systemic side effects. However, in some patients, even high doses of topical or even systemic GCs fail to control their disease. A number of mechanisms relating to inflammation have been reported to be responsible for the failure of these patients to respond correctly to GCs and these provide insight into GC actions within the airways. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed for these patients. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness.
Interleukin-4 and Lipopolysaccharide Synergize to Induce Vascular Cell Adhesion Molecule-1 Expression in Human Lung Microvascular Endothelial Cells
Publisher: American Thoracic Society
Date: 05-1998
Abstract: Recent studies suggest that increased vascular cell adhesion molecule-1 (VCAM-1) expression on vascular endothelium in bronchial mucosa biopsies correlates with interleukin-4 (IL-4) levels in bronchiolar lavage fluid of allergic asthmatics. The severity of asthma in patients allergic to house dust mite has also been shown to correlate with lipopolysaccharide (LPS), rather than allergen, concentration in dust. We hypothesized that to induce effective VCAM-1 expression in human lung microvascular endothelial cells (HLMVEC), IL-4 may require the presence of a co-stimulus such as LPS. To test this hypothesis we measured, by enzyme-linked immunosorbent assay, induction of cell adhesion molecule expression on, and human eosinophil adhesion to, cultured HLMVEC monolayers pretreated with IL-4 alone or combined with LPS. IL-4 synergized with LPS to induce VCAM-1 expression at 24, 48, or 72 h, whereas IL-4 alone induced expression at 72 h only. IL-4 did not induce expression of intercellular adhesion molecule-1 or E-selectin or alter LPS-induced expression of either. Pre-exposure of HLMVEC to LPS or IL-4 (1 h), followed by IL-4 or LPS, respectively (23 h), also induced VCAM-1 expression. Eosinophil adhesion to HLMVEC monolayers treated with IL-4 and LPS together, but not alone, significantly (P < 0.001) increased from 9.6 +/- 1.5% (control) to 26.9 +/- 3.3% and was inhibited by a monoclonal antibody against the VCAM-1 ligand, very late antigen-4. Analysis of VCAM-1 mRNA revealed synergism between IL-4 and LPS which may, in part, contribute to enhanced VCAM-1 expression. These results suggest that the presence of a co-stimulus such as LPS may be necessary for IL-4 to effectively induce VCAM-1 expression in lung microvasculature.
Highly Conserved Interaction Profiles between Clinically Relevant Mutants of the Cytomegalovirus CDK-like Kinase pUL97 and Human Cyclins: Functional Significance of Cyclin H
Publisher: MDPI AG
Date: 05-10-2022
Abstract: The complex host interaction network of human cytomegalovirus (HCMV) involves the regulatory protein kinase pUL97, which represents a viral cyclin-dependent kinase (CDK) ortholog. pUL97 interacts with the three human cyclin types T1, H, and B1, whereby the binding region of cyclin T1 and the pUL97 oligomerization region were both assigned to amino acids 231-280. We further addressed the question of whether HCMVs harboring mutations in ORF-UL97, i.e., short deletions or resistance-conferring point mutations, are affected in the interaction with human cyclins and viral replication. To this end, clinically relevant UL97 drug-resistance-conferring mutants were analyzed by whole-genome sequencing and used for genetic marker transfer experiments. The recombinant HCMVs indicated conservation of pUL97–cyclin interaction, since all viral UL97 point mutants continued to interact with the analyzed cyclin types and exerted wild-type-like replication fitness. In comparison, recombinant HCMVs UL97 Δ231-280 and also the smaller deletion Δ236-275, but not Δ241-270, lost interaction with cyclins T1 and H, showed impaired replication efficiency, and also exhibited reduced kinase activity. Moreover, a cellular knock-out of cyclins B1 or T1 did not alter HCMV replication phenotypes or pUL97 kinase activity, possibly indicating alternative, compensatory pUL97–cyclin interactions. In contrast, however, cyclin H knock-out, similar to virus deletion mutants in the pUL97–cyclin H binding region, exhibited strong defective phenotypes of HCMV replication, as supported by reduced pUL97 kinase activity in a cyclin H-dependent coexpression setting. Thus, cyclin H proved to be a very relevant determinant of pUL97 kinase activity and viral replication efficiency. As a conclusion, the results provide evidence for the functional importance of pUL97–cyclin interaction. High selective pressure on the formation of pUL97–cyclin complexes was identified by the use of clinically relevant mutants.
Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients
Publisher: Elsevier BV
Date: 06-2004
ERS Lung Science Conference 2016 report
Publisher: European Respiratory Society (ERS)
Date: 31-05-2016
Is mitochondrial dysfunction a driving mechanism linking COPD to nonsmall cell lung carcinoma?
Publisher: European Respiratory Society (ERS)
Date: 25-10-2017
DOI: 10.1183/16000617.0040-2017
Abstract: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of developing nonsmall cell lung carcinoma, irrespective of their smoking history. Although the mechanisms behind this observation are not clear, established drivers of carcinogenesis in COPD include oxidative stress and sustained chronic inflammation. Mitochondria are critical in these two processes and recent evidence links increased oxidative stress in COPD patients to mitochondrial damage. We therefore postulate that mitochondrial damage in COPD patients leads to increased oxidative stress and chronic inflammation, thereby increasing the risk of carcinogenesis. The functional state of the mitochondrion is dependent on the balance between its biogenesis and degradation (mitophagy). Dysfunctional mitochondria are a source of oxidative stress and inflammasome activation. In COPD, there is impaired translocation of the ubiquitin-related degradation molecule Parkin following activation of the Pink1 mitophagy pathway, resulting in excessive dysfunctional mitochondria. We hypothesise that deranged pathways in mitochondrial biogenesis and mitophagy in COPD can account for the increased risk in carcinogenesis. To test this hypothesis, animal models exposed to cigarette smoke and developing emphysema and lung cancer should be developed. In the future, the use of mitochondria-based antioxidants should be studied as an adjunct with the aim of reducing the risk of COPD-associated cancer.
Expression of nonmuscle cofilin-1 and steroid responsiveness in severe asthma
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1016/J.JACI.2006.07.039
Abstract: Glucocorticoids are the mainstay of asthma therapy however, a proportion of patients with asthma has a severe form of the disease that fails to respond to therapy. Understanding the molecular mechanisms behind glucocorticoid-insensitive asthma is therefore of clinical importance. Evidence in glucocorticoid-unresponsive Henrietta Lack (HeLa) cells indicated that cofilin-1 could act as an inhibitor of glucocorticoid function. To determine whether cofilin-1 expression is abnormally expressed in cells from patients with severe glucocorticoid-insensitive asthma and examine the effect of cofilin-1 overexpression on glucocorticoid function. Peripheral blood CD4(+) T cells were purified from 16 subjects with severe glucocorticoid-insensitive asthma and 16 subjects with mild glucocorticoid-sensitive asthma, and cofilin-1 expression was determined by quantitative real-time RT-PCR and Western blotting. The effect of dexamethasone on cofilin-1 expression was determined in Jurkat T cells, and the effect of cofilin-1 overexpression on anti-CD3/CD28-stimulated IL-2 release was measured. Peripheral blood CD4(+) T cells from subjects with severe glucocorticoid-insensitive asthma are less responsive to dexamethasone than cells from subjects with mild glucocorticoid-sensitive asthma. Cells from these patients express significantly (P < .05) higher levels of cofilin-1 than cells from subjects with mild asthma. Dexamethasone did not affect cofilin-1 expression in Jurkat T cells. Functionally, dexamethasone suppression of anti-CD3/CD28-stimulated IL-2 was attenuated in Jurkat cells overexpressing cofilin-1. These results suggest that increased cofilin-1 expression may be important in the regulation of glucocorticoid sensitivity in peripheral blood lymphocytes of patients with severe treatment-insensitive asthma. Understanding the mechanisms of enhanced cofilin-1 expression may lead to the development of new therapies for severe treatment-insensitive asthma.
Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages
Publisher: Wiley
Date: 04-2001
Effects of interleukin-1β, interleukin-13 and transforming growth factor-β on gene expression in human airway smooth muscle using gene microarrays
Publisher: Elsevier BV
Date: 08-2004
Mechanisms involved in lung cancer development in COPD
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.BIOCEL.2010.08.022
Abstract: Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. COPD is also a major independent risk factor for lung carcinoma, among long-term smokers. Smokers with COPD also have a higher risk of developing a specific histological subtype of non-small cell lung cancer termed squamous cell carcinoma. For these reasons the focus of this review is on the potential pathogenic molecular links between tobacco smoking-related COPD and squamous cell carcinoma. We believe that we need to promote more studies on the molecular and cellular pathobiology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies should also look at younger healthy smokers in combination with risk models of lung cancer and COPD. Overall these studies may allow the discovery of new molecular targets of the early carcinogenesis process that in the foreseeable future may render the early diagnosis and treatment, and may be even the prevention, of invasive squamous cell lung carcinoma a reality.
Inducible nitric oxide synthase is increased in murine lung epithelial cells by cytokine stimulation.
Publisher: Elsevier BV
Date: 02-1994
Abstract: Nitric oxide (NO) is detectable in exhaled air. To elucidate whether airway epithelial cells could be a source of NO, we investigated the expression of inducible nitric oxide synthase (iNOS) by the murine lung epithelial cell line, LA-4, in response to cytokine stimulation and the ability of corticosteroids to modulate this effect. Stimulation with cytomix, a combination of interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma, elevated nitrite levels by 873% in the culture supernatants and enhanced the conversion of arginine to citrulline by 273% at 24 h. An increased number of cells stained for iNOS and an increase in iNOS mRNA was also observed. Dexamethasone decreased the cytokine-induced increase in nitrite levels, NOS activity, iNOS immunoreactivity, and mRNA but did not change the half life of iNOS mRNA. These results show that lung epithelial cells can release NO, a process which can be inhibited by dexamethasone.
M048 Clinical characteristic of severe asthma patients with JAK-STAT pathway activation
Publisher: Elsevier BV
Date: 05-2022
Suppression of GATA-3 Nuclear Import and Phosphorylation: A Novel Mechanism of Corticosteroid Action in Allergic Disease
Publisher: Public Library of Science (PLoS)
Date: 19-05-2009
Changes in targeted metabolomics in lung tissue of chronic obstructive pulmonary disease
Publisher: AME Publishing Company
Date: 05-2023
DOI: 10.21037/JTD-22-1731
Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.JACI.2021.10.003
Abstract: Obesity is a risk factor for asthma, and obese asthmatic in iduals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described. We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain-containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet-induced obesity and asthma. Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet-induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet-induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine-targeted biologics and inflammasome inhibitors.
An early innate response underlies severe influenza‐induced exacerbations of asthma in a novel steroid‐insensitive and anti‐IL ‐5‐responsive mouse model
Publisher: Wiley
Date: 10-11-2016
DOI: 10.1111/ALL.13057
Abstract: Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model h ers mechanistic insight and the development of new therapeutics. We developed and characterized a robust, consistent, and reproducible mouse model of severe exacerbation of chronic allergic asthma. Chronic allergic airway inflammation was induced following a house dust mite (HDM) sensitization protocol. HDM-sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled fluticasone propionate (FP), systemic corticosteroids (Pred), or anti-IL-5. Mice were killed at different time points after infection: Cellular accumulation and cytokines levels in the airways, PenH as a measure of airway hyper-responsiveness (AHR), and lung histology and viral replication were assessed. Infection with low-dose A/X31 H3N2 led to prolonged deterioration of lung function, aggravated mucus production, peri-vascular, peri-bronchial, and allergic inflammation that was unresponsive to inhaled corticosteroids, but responsive to systemic corticosteroids. The exacerbation was preceded at 14 h after virus exposure by a marked innate, but no Th2 and Th1 response subsequently followed by enhanced numbers of eosinophils, neutrophils, dendritic, and T cells into the lung lumen, parenchyma, and draining lymph nodes in HDM-sensitized mice. Anti-IL-5 treatment attenuated eosinophils and prevented the X31-induced exacerbation. Together, these findings indicate that an early innate response that involves eosinophils underlies the exacerbation. This model recapitulates all major features of severe asthma exacerbations and can serve to discern driving mechanisms and promote the development of novel therapeutics.
Large-Scale Label-Free Quantitative Mapping of the Sputum Proteome
Publisher: American Chemical Society (ACS)
Date: 08-05-2018
DOI: 10.1021/ACS.JPROTEOME.8B00018
Abstract: Analysis of induced sputum supernatant is a minimally invasive approach to study the epithelial lining fluid and, thereby, provide insight into normal lung biology and the pathobiology of lung diseases. We present here a novel proteomics approach to sputum analysis developed within the U-BIOPRED (unbiased biomarkers predictive of respiratory disease outcomes) international project. We present practical and analytical techniques to optimize the detection of robust biomarkers in proteomic studies. The normal sputum proteome was derived using data-independent HDMS
Increased p21CIP1/WAF1and B Cell Lymphoma Leukemia-xLExpression and Reduced Apoptosis in Alveolar Macrophages from Smokers
Publisher: American Thoracic Society
Date: 09-2002
DOI: 10.1164/RCCM.2104010
Abstract: Alveolar macrophages (AMs) are the predominant defense cells in the airway, and their numbers are increased in smokers and subjects with chronic obstructive pulmonary disease. This increase may result from increased recruitment, increased proliferation, or reduced cell death. Apoptosis regulates inflammatory cell survival, and p21(CIP1/WAF1) is an important inhibitory regulator of cycle progression after oxidative stress. We have investigated whether chronic smoke exposure influences the expression and localization of cell cycle and apoptotic proteins in AM and bronchial epithelial cells in vivo. The increased numbers of AMs seen in smokers were only partially due to enhanced proliferation. p21(CIP1/WAF1) protein expression was increased in AMs and biopsies isolated from smokers and was found predominantly within the cytoplasm. In addition, B cell lymphoma leukemia (Bcl)-x(L), an antiapoptotic regulator, was also highly expressed in macrophages from smokers compared with nonsmokers and subjects with asthma. Hydrogen peroxide, an oxidative stress, induced cytoplasmic expression of p21(CIP1/WAF1) and failed to induce apoptosis in an in vitro model. These results suggested that AM and bronchial epithelial cells from smokers, in contrast to those from normal subjects and subjects with asthma, have reduced cell death. Thus, oxidative stress induced by cigarette smoking may contribute to the chronicity of inflammation in the airway, through a reduction of apoptosis.
Sputum gene signature comparison study between U-BIOPRED and Australia asthma cohorts
Publisher: European Respiratory Society
Date: 28-09-2019
Induction of macrophage inflammatory protein 2 gene expression by interleukin 1 beta in rat lung.
Publisher: BMJ
Date: 11-1995
Abstract: Recruitment of inflammatory cells in the lungs may contribute to tissue injury as a result of mediators released from these cells. Interleukin 1 beta (IL-1 beta) is a potent inducer of neutrophil accumulation, a process that may require local protein biosynthesis. Macrophage inflammatory protein 2 (MIP-2) is a approximately 6 kD heparin binding protein and is a member of the C-X-C superfamily that causes significant neutrophil chemotaxis and activation in vitro. A study was performed to determine whether IL-1 beta could induce the expression of MIP-2 in the lungs of Brown-Norway rats. rhIL-1 beta (500 U) or 0.9% NaCl was injected intratracheally and bronchoalveolar lavage (BAL) cells and lung tissues were evaluated for MIP-2 mRNA expression after RNA extraction by Northern blot analysis. MIP-2 probe was prepared from cDNA obtained by reverse transcriptase-polymerase chain reaction (RT-PCR) of BAL cells obtained from a rat treated with lipopolysaccharide. There was no detectable MIP-2 mRNA in the lungs of control rats but a marked enhancement of the expression at four hours with no expression at 12 hours and a slight expression at 24 hours. IL-1 beta induced a significant influx of neutrophils into BAL fluid with a transient increase in macrophages. In situ hybridisation of lungs using MIP-2 cDNA probe labelled with digoxigenin showed expression of MIP-2 mRNA in airway mononuclear cells and airway epithelium at four hours after IL-1 beta at 24 hours the signal had nearly gone. IL-1 beta induces the expression of MIP-2 mRNA in rat lung. MIP-2 may be one chemokine that could contribute to IL-1 beta induced neutrophil influx.
Autoimmunity and COPD
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CHEST.2017.10.033
Abstract: COPD is a leading cause of morbidity and mortality worldwide. Long-term cigarette smoking is the cause of > 90% of COPD cases in Westernized countries. However, only a fraction of chronic heavy smokers develop symptomatic COPD by age 80. COPD is characterized by an abnormal immune response in the lower airways, and its progression is associated with infiltration of the lung by innate and adaptive inflammatory immune cells that form lymphoid follicles. There is growing evidence that both cellular- and antibody-mediated autoimmunity has a fundamental role in the pathogenesis of stable COPD. In particular, carbonyl-modified proteins may help to drive autoimmunity in COPD and cause the characteristic small airways abnormalities and even contribute to the pathogenesis of pulmonary emphysema. Although direct, indirect, and circumstantial evidence of a role for autoimmunity in stable patients with COPD has been identified, no cause-and-effect relationship between autoimmunity and the mechanisms of COPD has been firmly established in man. As such, the potential contribution of an autoimmune response to the pathogenesis of COPD exacerbation is still being investigated and represents an area of active research. Many drugs targeting autoimmune responses are already available, and the results of controlled clinical trials are awaited with great interest. The potential for measuring specific serum autoantibodies as biomarkers to predict clinical phenotypes or progression of stable COPD is promising.
CSF3R/CD114 mediates infection-dependent transition to severe asthma.
Publisher: Elsevier BV
Date: 02-2018
MiRNAs in tuberculosis: Their decisive role in the fate of TB
Publisher: Elsevier BV
Date: 11-2020
A data management and analysis platform for RASP-UK multiomics clinical datasets
Publisher: European Respiratory Society
Date: 05-09-2021
Inferring Cell-Scale Signalling Networks via Compressive Sensing
Publisher: Public Library of Science (PLoS)
Date: 18-04-2014
Epithelial-stromal cell interactions and ECM mechanics drive the formation of airway-mimetic tubular morphology in lung organoids
Publisher: Cold Spring Harbor Laboratory
Date: 03-12-2020
DOI: 10.1101/2020.12.03.408815
Abstract: The complex cellular organisation of the human airway tract where interaction between epithelial and stromal lineages and the extracellular matrix (ECM) make it a difficult organ to study in vitro . Current in vitro lung models focus on modelling the lung epithelium such as air-liquid interface (ALI) cultures and bronchospheres, do not model the complex morphology and the cell-ECM interaction seen in vivo . Models that include stromal populations often separate them via a semipermeable barrier, which precludes the effect of cell-cell interaction or do not include the ECM or the effect of ECM mechanics such as viscoelasticity and stiffness. Here we investigated the effect of stromal cells on basal epithelial cell-derived bronchosphere structure and function through a triple culture of bronchial epithelial, lung fibroblast and airway smooth muscle cells. Epithelial-stromal cross talk enabled formation of epithelial cell-driven branching tubules consisting of luminal epithelial cells surrounded by stromal cells termed bronchotubules. Addition of agarose to the Matrigel scaffold (Agrigel) created a mechanically tunable ECM, where viscoelasticity and stiffness could be altered to enable long term tubule survival. Bronchotubule models enable the investigation of how epithelial-stromal cell and cell-ECM communication drive tissue patterning, repair and development of disease. Current models of airways diseases such as asthma and COPD do not reflect the physical characteristics of the diseased airway which may impact upon our understanding of disease pathophysiology. We have utilised the physical properties of agarose to modify the 3D stiffness of Matrigel to resemble the human airway. Using a primary airway epithelial cell-derived organoid model we demonstrate that a combined Matrigel/agrigel matrix allows sustained 3D organoid structure and the creation of tubules that can contract in response to a clinically relevant bronchoconstrictor. A complex 3D organoid composed of functioning epithelial cells, smooth muscle cells and fibroblasts may provide opportunities for refined drug discovery programmes. Mixture of healthy lung basal epithelial cells and healthy lung fibroblast cultured in matrigel result in tubules that fail in 4 days. Addition of healthy airway smooth muscle allows for a contractile phenotype. Triple culture of cells in a stiffer scaffold agrigel allows maintenance of tubular organoids for a minimum of 20 days.
IL-1β and TNF-α Regulation of the Adenosine Receptor (A2A) Expression: Differential Requirement for NF-κB Binding to the Proximal Promoter
Publisher: The American Association of Immunologists
Date: 15-11-2006
DOI: 10.4049/JIMMUNOL.177.10.7173
Abstract: Adenosine is a potent endogenous regulator of airway inflammation that acts through specific receptor subtypes that can either cause constriction (A1R, A2BR, and A3R) or relaxation (A2AR) of the airways. We therefore examined the effects of key inflammatory mediators on the expression of the A2AR in a lung epithelial cell line (A549). IL-1β and TNF-α increased the expression of the A2AR gene at the mRNA and protein levels. In contrast, LPS had no effect on A2AR gene expression. IL-1β and TNF-α rapidly activated p50 and p65, but not C-Rel, RelB, or p52, and both IL-1β- and TNF-α-stimulated A2AR expression was inhibited by the IκB kinase 2 inhibitor AS602868 in a concentration-dependent manner. Using chromatin immunoprecipitation assays, we demonstrate that IL-1β can enhance p65 association with putative κB binding sites in the A2AR promoter in a temporal manner. In contrast, TNF-α failed to enhance p65 binding to these putative sites. Functionally, the two most 5′ κB sites were important for IL-1β-, but not TNF-α-, induced A2AR promoter reporter gene activity. Finally, neither TNF-α nor Il-1β had any effect on A2AR mRNA transcript degradation. These results directly implicate a major role for NF-κB in the regulation of A2AR gene transcription by IL-1β and TNF-α but suggest that the effects of TNF-α on A2AR gene transcription are not mediated through the proximal promoter.
CEACAM5 is an IL ‐13‐regulated epithelial gene that mediates transcription in type‐2 (T2 ) high severe asthma
Publisher: Wiley
Date: 12-08-2022
DOI: 10.1111/ALL.15465
Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.EJPHAR.2018.11.010
Abstract: Fine particulate matter (PM
Transcription inhibitors and inflammatory cell activity
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.COPH.2019.05.006
Abstract: Inflammation is a central feature of asthma and chronic obstructive pulmonary disease (COPD). Despite recent advances in the knowledge of the pathogenesis of asthma and COPD, much more research on the molecular mechanisms of asthma and COPD are needed to aid the logical development of new therapies for these common and important diseases, particularly in COPD where no new effective treatments currently exist. In the future the role of the activation/repression of different transcription factors and the genetic regulation of their expression in asthma and COPD may be an increasingly important aspect of research, as this may be one of the critical mechanisms regulating the expression of different clinical phenotypes and their responsiveness to therapy, particularly to anti-inflammatory drugs.
Dexamethasone action on c-fos and c-jun mRNA and protein in human lung
Publisher: Portland Press Ltd.
Date: 05-1994
DOI: 10.1042/BST022187S
Angiogenic effects of cell therapy within a biomaterial scaffold in a rat hind limb ischemia model
Publisher: Springer Science and Business Media LLC
Date: 15-10-2021
DOI: 10.1038/S41598-021-99579-0
Abstract: Critical limb ischemia (CLI) is a life- and limb-threatening condition affecting 1–10% of humans worldwide with peripheral arterial disease. Cellular therapies, such as bone marrow-derived mesenchymal stem cells (MSCs) have been used for the treatment of CLI. However, little information is available regarding the angiogenic potency of MSCs and mast cells (MC) in angiogenesis. The aim of this study was to evaluate the ability of MCs and MSCs to induce angiogenesis in a rat model of ischemic hind limb injury on a background of a tissue engineered hydrogel scaffold. Thirty rats were randomly ided into six control and experimental groups as follows: (a) Control healthy (b) Ischemic positive control with right femoral artery transection, (c) ischemia with hydrogel scaffold, (d) ischemia with hydrogel plus MSC, (e) ischemia with hydrogel plus MC and (f) ischemia with hydrogel plus MSC and MCs. 10 6 of each cell type, isolated from bone marrow stroma, was injected into the transected artery used to induce hind limb ischemia. The other hind limb served as a non-ischemic control. After 14 days, capillary density, vascular diameter, histomorphometry and immunohistochemistry at the transected location and in gastrocnemius muscles were evaluated. Capillary density and number of blood vessels in the region of the femoral artery transection in animals receiving MSCs and MCs was increased compared to control groups (P 0.05). Generally the effect of MCs and MSCs was similar although the combined MC/MSC therapy resulted in a reduced, rather than enhanced, effect. In the gastrocnemius muscle, immunohistochemical and histomorphometric observation showed a great ratio of capillaries to muscle fibers in all the cell-receiving groups (P 0.05). The data indicates that the combination of hydrogel and cell therapy generates a greater angiogenic potential at the ischemic site than cell therapy or hydrogels alone.
Glucocorticoid Actions on Airway Smooth Muscle
Publisher: Wiley
Date: 18-04-2008
Barnes and Adcock reply
Publisher: Elsevier BV
Date: 05-1994
Anti-inflammatory actions of steroids: molecular mechanisms
Publisher: Elsevier BV
Date: 12-1993
DOI: 10.1016/0165-6147(93)90184-L
Abstract: Glucocorticosteroids are highly effective in controlling inflammation and the molecular mechanisms involved are now becoming clear. Activation of glucocorticoid receptors results in increased or decreased transcription of a number of genes involved in the inflammatory process. Of particular importance is the repression of cytokine gene transcription and the direct interaction between the glucocorticoid receptor and other transcription factors activated in chronic inflammation. In this review, Peter Barnes and Ian Adcock discuss recent studies that have increased our understanding of these mechanisms and that may lead to improved anti-inflammatory therapies in the future.
Oxidative stress induces NFkB DNA binding and inducible NOS mRNA in the human epithelial cell line A549
Publisher: Portland Press Ltd.
Date: 05-1994
DOI: 10.1042/BST022186S
Abstract: Delayed sternal closure is used in paediatric cardiac surgery as a management strategy for patients with unstable hemodynamics or postoperative bleeding routinely. We hypothesise that planned postponement of sternal closure leads to better outcomes than emergent reopening in the intensive care unit (ICU) in patients exhibiting some hemodynamic indication for the same. We retrospectively analysed the outcomes of delayed sternal closure 220/2111 (10.42%) out of which 14 sternums were opened in the ICU after shifting the patients. A total of 220/2111 (10.42%) sternums were left open postoperatively, out of which 14 were opened after shifting to the ICU. Total mortality of the delayed sternal closure was 33/220, i.e. 15%. The patients whose sternums were left open from the theatre had a mortality of 23/206, i.e. 11.16%, whereas those patients whose sternums were opened in the ICU had a mortality of 10/14, i.e. 71.42%. In doubtful postoperatively hemodynamic, the choice of leaving the sternum open electively has better outcomes, rather than opening the sternum as a terminal bail out procedure.
Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.BBRC.2009.04.128
Abstract: Histone deacetylases (HDACs) are key molecules involved in epigenetic regulation of gene expression. We have previously demonstrated that oxidative stress caused a reduction in HDAC2, resulting in lified inflammation and reduced corticosteroid responsiveness. Here we showed nitrative/oxidative stress reduced HDAC2 expression via nitration of distinct tyrosine residues. Peroxynitrite, hydrogen peroxide and cigarette smoke-conditioned medium reduced HDAC2 expression in A549 epithelial cells in vitro. This reduction was due to increased proteasomal degradation following ubiquitination rather than reduction of mRNA expression or stability. HDAC2 was nitrated under nitrative/oxidative stress and in the peripheral lung tissues of smokers and patients with chronic obstructive pulmonary disease. Mutagenesis studies replacing tyrosine (Y) residues with alanine revealed that Y253 is at least partly responsible for the proteasomal degradation of HDAC2 under nitrative stress. Thus, nitration of distinct tyrosine residues modifies both the expression and activity of HDAC2, having an impact on epigenetic regulation.
2018 CIS Annual Meeting: Immune Deficiency & Dysregulation North American Conference
Publisher: Springer Science and Business Media LLC
Date: 04-2018
p38 Mitogen-activated protein kinase–induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma
Publisher: Elsevier BV
Date: 04-2002
Abstract: Although glucocorticoids are the most effective treatment for chronic inflammatory diseases, such as asthma, some patients show a poor response. IL-2 combined with IL-4 can alter glucocorticoid receptor (GR) ligand-binding affinity and modulate glucocorticoid function. We sought to confirm the altered ligand-binding affinity in a distinct group of steroid-dependent asthmatic subjects and examine the mechanism by which IL-2 and IL-4 modify the ligand-binding affinity of the GR. We examined PBMCs from healthy subjects, subjects with mild asthma, and steroid-dependent subjects with severe asthma using dexamethasone-binding assays and Western blot analysis of GR and phosphorylated activated transcription factor 2 expression. GR phosphorylation was measured after orthophosphate labeling and immunoprecipitation and cytokine production by means of ELISA. GR ligand-binding affinity was reduced in the nucleus but not in the cytoplasm of steroid-dependent asthmatic subjects compared with that seen in healthy subjects (dissociation constant, 39.8 +/- 4.6 vs. 6.79 +/- 0.8 nmol/L). This difference in ligand-binding affinity could be mimicked by IL-2 and IL-4 cotreatment and was blocked by the p38 mitogen-activated kinase (MAPK) inhibitor SB203580. Activation of p38 MAPK by IL-2 and IL-4, as shown by means of phosphorylation of activated transcription factor 2, resulted in GR phosphorylation and reduced dexamethasone repression of LPS-stimulated GM-CSF release. p38 MAPK phosphorylation of CD2(+) T cells occurred on serine residues. The ability of dexamethasone to modulate IL-10 release was also inhibited by IL-2 and IL-4 cotreatment. These effects were also inhibited by SB203580. These data show that p38 MAPK inhibitors may have potential in reversing glucocorticoid insensitivity and reestablishing the beneficial effects of glucocorticoids in patients with severe asthma.
Decreased serum levels of angiotensin converting enzyme (ACE)2 and enhanced cytokine levels with severity of COVID-19: normalisation upon disease recovery
Publisher: Elsevier BV
Date: 02-2022
Molecular links between COPD and lung cancer: new targets for drug discovery?
Publisher: Informa UK Limited
Date: 11-05-2019
DOI: 10.1080/14728222.2019.1615884
Abstract: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation. Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer. Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.
Decision support system to evaluate ventilation in the acute respiratory distress syndrome (DeVENT study)—trial protocol
Publisher: Springer Science and Business Media LLC
Date: 17-01-2022
DOI: 10.1186/S13063-021-05967-2
Abstract: The acute respiratory distress syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator-induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the in idual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using in idual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS. We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS. Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator-induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic) could change the outcome of mechanically ventilated patients during the course of this and future pandemics. ClinicalTrials.gov identifier NCT04115709. Registered on 4 October 2019, version 4.0
MicroRNAs in Human Disease: Commentary
Publisher: Knowledge E
Date: 08-06-2021
DOI: 10.18502/IJAAI.V20I3.6341
Abstract: The Articles Abstract is not available.
Lung cells from people with COPD are hyperresponsive to E-cigarette vapour
Publisher: European Respiratory Society
Date: 15-09-2018
Budesonide facilitates weaning from mechanical ventilation in difficult-to-wean very severe COPD patients: Association with inflammatory mediators and cells
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.JCRC.2017.10.045
Abstract: Mechanical ventilatory support is life-saving therapy for patients with respiratory failure in intensive care units (ICU) but is linked to ventilator-associated pneumonia and other nosocomial infections. Interventions that improve the efficiency of weaning from mechanical ventilation may improve patient outcomes. To determine whether inhaled budesonide decreases time-to-weaning in COPD stage 4 difficult-to-wean patients and reduces the release of pro-inflammatory cytokines in ICU patients. We recruited 55 difficult-to-wean COPD patients (Stage 4) within the ICU of the Masih Daneshvari Hospital. Subjects were randomly assigned to receive inhaled budesonide (0.5mg/day) or placebo (normal saline). Dynamic compliance and BAL cytokines were measured. Budesonide significantly reduced the number of days on MV (days-to-weaning=4.6±1.6days) compared to that seen in the control group (7.2±2.7days, p=0.014). Dynamic compliance was significantly improved in the budesonide group on days 3 (p=0.018) and 5 (p=0.011) The levels of CXCL-8 and IL-6 diminished on days 3-5 after start of budesonide (p<0.05). In COPD patients on MV, nebulized budesonide was associated with reduced BAL CXCL8 and IL-6 levels and neutrophil numbers as well as an improvement in ventilatory mechanics and facilitated weaning.
Susceptibility to influenza virus infection of bronchial biopsies in asthma
Publisher: Elsevier BV
Date: 07-2017
Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma
Publisher: Springer Science and Business Media LLC
Date: 07-01-2021
DOI: 10.1186/S12931-020-01605-8
Abstract: Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells. We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels. ACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing s les, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes. Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.
13th European Respiratory Society Annual Congress
Publisher: Informa Healthcare
Date: 12-2003
IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis
Publisher: European Respiratory Society (ERS)
Date: 13-06-2019
DOI: 10.1183/13993003.00174-2018
Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis. Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients. However, its roles in the pathogenesis of COPD is poorly understood. Here, we investigated the role of IL-22 in human COPD and in cigarette smoke (CS)-induced experimental COPD. IL-22 and IL-22 receptor mRNA expression and protein levels were increased in COPD patients compared to healthy smoking or non-smoking controls. IL-22 and IL-22 receptor levels were increased in the lungs of mice with experimental COPD compared to controls and the cellular source of IL-22 included CD4 + T-helper cells, γδ T-cells, natural killer T-cells and group 3 innate lymphoid cells. CS-induced pulmonary neutrophils were reduced in IL-22-deficient ( Il22 −/− ) mice. CS-induced airway remodelling and emphysema-like alveolar enlargement did not occur in Il22 −/− mice. Il22 −/− mice had improved lung function in terms of airway resistance, total lung capacity, inspiratory capacity, forced vital capacity and compliance. These data highlight important roles for IL-22 and its receptors in human COPD and CS-induced experimental COPD.
Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD
Publisher: Bentham Science Publishers Ltd.
Date: 04-2021
DOI: 10.2174/0929867327999200819145327
Abstract: Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors (such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)) in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management.
Glucocorticoid Receptor Nuclear Translocation in Airway Cells after Inhaled Combination Therapy
Publisher: American Thoracic Society
Date: 15-09-2005
The BET Bromodomain Inhibitor I-BET-151 Induces Structural and Functional Alterations of the Heart Mitochondria in Healthy Male Mice and Rats
Publisher: MDPI AG
Date: 27-03-2019
DOI: 10.3390/IJMS20071527
Abstract: The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications.
Interactions of glucocorticoids and beta 2-agonists
Publisher: European Respiratory Society (ERS)
Date: 1996
DOI: 10.1183/09031936.96.09010160
Abstract: Beta 2-adrenoreceptor agonists and glucocorticosteroids are the two most effective treatments for asthma and are often used in combination. Glucocorticoids mediate their anti-inflammatory effects through the action of activated glucocorticoid receptors (GRs). Many of the effects of GRs on the synthesis of cytokines and other inflammatory mediators are due to a direct interaction with other deoxyribonucleic acid (DNA)-binding proteins belonging to the basic leucine zipper (bZIP) group of transcription factors, such as activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B). Beta 2-agonists are potent bronchodilators at low doses and at high doses can activate gene transcription via a bZIP protein, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Activated GRs and CREB can interact with each other within the nucleus to modulate both DNA-binding and gene transcription in either a positive or inhibitory manner, depending on cell type. In lung cells, high doses of beta 2-agonists reduce the ability of GR to bind DNA, a process which is mediated by CREB activation. Inhibition of GR DNA-binding by CREB raises the possibility that high-dose beta 2-agonists could have functional antiglucocorticoid activity and may be a basis for the reported increase in asthma morbidity and mortality in industrialized countries, which have increasing per capita beta 2-agonist use.
Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer
Publisher: BMJ
Date: 02-04-2011
Abstract: Chronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent protein kinase complex. To investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells. Protein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays. 8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p = 0.0012) and patients with COPD (p < 0.0148). Nuclear expression of Ku86, but not of DNA-PKcs, phospho-DNA-PKcs, Ku70 or γ-H2AFX, was reduced in bronchiolar epithelial cells from patients with COPD compared with normal smokers and non-smokers (p < 0.039). Loss of Ku86 expression was also observed in a smoking mouse model (p < 0.012) and prevented by antioxidants. Oxidants reduced (p < 0.0112) Ku86 expression in human bronchial epithelial cells and Ku86 knock down modified AP sites in response to oxidative stress. Ineffective DNA repair rather than strand breakage per se accounts for the reduced AP sites observed in COPD and this is correlated with a selective decrease of the expression of Ku86 in the bronchiolar epithelium. DNA damage/repair imbalance may contribute to increased risk of lung carcinoma in COPD.
Cellular and molecular features of COVID-19 associated ARDS: therapeutic relevance
Publisher: Springer Science and Business Media LLC
Date: 20-03-2023
DOI: 10.1186/S12950-023-00333-2
Abstract: The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic or cause a disease (COVID-19) characterized by different levels of severity. The main cause of severe COVID-19 and death is represented by acute (or acute on chronic) respiratory failure and acute respiratory distress syndrome (ARDS), often requiring hospital admission and ventilator support. The molecular pathogenesis of COVID-19-related ARDS (by now termed c-ARDS) is still poorly understood. In this review we will discuss the genetic susceptibility to COVID-19, the pathogenesis and the local and systemic biomarkers correlated with c-ARDS and the therapeutic options that target the cell signalling pathways of c-ARDS.
Expression and Activity of Histone Deacetylases in Human Asthmatic Airways
Publisher: American Thoracic Society
Date: 08-2002
DOI: 10.1164/RCCM.2110060
Abstract: Asthma is a chronic inflammatory disease that is characterized by increased expression of multiple inflammatory genes. Chromatin modification plays a critical role in the regulation of these genes. Acetyaltion of histones by histone acetyltransferases (HATs) is associated with increased gene transcription, whereas hypocetylation induced by histone deacetylases (HDACs) is associated with suppression of gene expression. We have examined the expression and activity of HATs and HDACs in bronchial biopsies from normal subjects and subjects with asthma. There was no difference in the site of HDAC1-HDAC6 expression between normal subjects and subjects with asthma, but subjects with asthma had reduced HDAC enzymatic activity and reduced HDAC1 and HDAC2 protein expression, as measured by Western blotting. In contrast, subjects with asthma treated with inhaled steroids were found to have greater HDAC activity than untreated subjects with asthma, although still lower than control subjects. In contrast, although there was no change in the site of HAT (CREB binding protein and p300/CREB binding protein-associated factor) expression, HAT activity was increased in subjects with asthma. HAT activity was reduced to control levels in subjects with asthma treated with inhaled steroids. The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes, and this is reversed, at least in part, by treatment with inhaled steroids.
Sexual dimorphism of messenger RNA isolated from neonatal rat brain
Publisher: Bioscientifica
Date: 04-1986
Abstract: The rat brain is sexually dimorphic with respect to structure and function, and there is evidence that these differences are effected in the fetus through changes in protein synthesis, some of which may result from the intervention of gonadal steroids. To investigate this, messenger RNA (mRNA) from the limbic system and cerebellum of neonatal rats was prepared, translated in a rabbit reticulocyte system in vitro and the products were analysed by two-dimensional electrophoresis and fluorography. Some of the results were further analysed using image analysis. There was a striking sexual dimorphism in the patterns of incorporation of [ 35 S]methionine into proteins using mRNA from the limbic system, in that groups of proteins were apparently present in male-but not in female-derived fluorograms and vice versa . One protein, tentatively identified from its coordinates as α-tubulin, was more abundant in male-derived fluorograms. Although there were no clear-cut qualitative sex differences using mRNA derived from the cerebellum, that derived from the male cerebellum appeared to be consistently more active. These results provide direct evidence for a sexual dimorphism at the transcriptional level in the neonatal limbic system of the rat. J. Endocr. (1986) 109, 23–28
Modulation of LPS stimulated NF-kappaB mediated Nitric Oxide production by PKCε and JAK2 in RAW macrophages
Publisher: Springer Science and Business Media LLC
Date: 24-11-2007
Abstract: Nuclear factor kappa B (NF-κB) has been shown to play an important role in regulating the expression of many genes involved in cell survival, immunity and in the inflammatory processes. NF-κB activation upregulates inducible nitric oxide synthase leading to enhanced nitric oxide production during an inflammatory response. NF-κB activation is regulated by distinct kinase pathways independent of inhibitor of κB kinase (IKK). Here, we examine the role of protein kinase C isoforms and janus activated kinase 2 (JAK2) activation in NF-κB activation and LPS-stimulated NO production. Murine RAW 264.7 macrophages were treated with lipopolysaccharide (LPS), Phorbol 12-myristate 13-acetate (PMA) and a combination of LPS and PMA in the presence or absence of various inhibitors of PKC isoforms and JAK2. Nuclear translocation of the NF-κB p65 subunit, was assessed by Western blot analysis whilst NO levels were assessed by Greiss assay. LPS-stimulated NO production was attenuated by PMA whilst PMA alone did not affect NO release. These effects were associated with changes in p65 nuclear translocation. The PKCα, β, γ, δ and ζ inhibitor Gö 6983 (Go) had no effect on LPS-induced NO release. In contrast, Bisindolymalemide I (Bis), a PKC α, β I , β II , γ, δ and ε isoform inhibitors completely inhibited LPS-stimulated NO production without affecting p65 nuclear translocation. Furthermore, a partial inhibitory effect on LPS-induced NO release was seen with the JAK2 inhibitor AG-490 and the p38 MAPK inhibitor SB 203850. The results further define the role of NF-κB in LPS stimulated NO production in RAW macrophages. The data support a function for PKCε, JAK2 and p38 MAPK in NF-κB activation following p65 nuclear import.
BET proteins are a key component of immunoglobulin gene expression
Publisher: Future Medicine Ltd
Date: 04-2017
Abstract: Aim: BET proteins have been shown to regulate gene expression including inflammatory genes. Methods: In order to investigate the role of the BET proteins in immunoglobulin production we treated the human B-cell line CLNH11.4 and primary human B cells and ozone-exposed mice with BET inhibitors (JQ1 or IBET151). Results: Both proliferation and IgG production were reduced by JQ1 in a concentration-dependent manner. JQ1 significantly reduced immunoglobulin gene transcription. In vivo treatment of ozone-exposed mice with the BET inhibitor IBET151 similarly inhibited ozone-induced immunoglobulin production. JQ1 did not reduce the protein levels of Brd4 or Oct2 per se but reduced the ability of Brd4 and Oct2 to co-immunoprecipitate and of Oct2 to bind to immunoglobulin gene promoters. Conclusion: Our results indicate that BET proteins including Brd4 play a crucial role regulation B-cell-specific gene expression and immunoglobulin production.
Endotoxin and steroid effects on nitric oxide synthase mRNA expression in rat lung and other tissues
Publisher: Portland Press Ltd.
Date: 05-1994
DOI: 10.1042/BST022188S
TNFAIP3 (A20) expression is elevated in the sputum of severe asthmatics
Publisher: European Respiratory Society
Date: 09-2016
The first U-BIOPRED blood handprint of severe asthma
Publisher: European Respiratory Society
Date: 09-2015
Type 2‐low asthma phenotypes by integration of sputum transcriptomics and serum proteomics
Publisher: Wiley
Date: 16-09-2020
DOI: 10.1111/ALL.14573
Roles of TRPA1 and TRPV1 in cigarette smoke -induced airway epithelial cell injury model
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.FREERADBIOMED.2019.01.004
Abstract: Transient receptor potential protein (TRP) ion channels TRPA1 and TRPV1 may be important in mediating airway tissue injury and inflammation. This study was designed to clarify the role of TRPA1 and TRPV1 channels in cigarette smoke extract (CSE)-induced damage to bronchial and alveolar epithelial cells. Alveolar epithelial (A549) cells and bronchial epithelial (Beas-2B) cells were treated with CSE in the presence and absence of a TRPA1 inhibitor (100 μM, A967079), a TRPV1 inhibitor (100 μM, AMG9810) or both. DCFH-DA and MitoSOX Red probes were used to assay intracellular and mitochondrial oxidative stress, respectively. The mRNA levels of inflammatory mediators (IL-1β, IL-8, IL-18, IL-33) and antioxidants (HO-1, NQO1, MnSOD, catalase) and the protein expression levels of mitochondrial and inflammasome factors (MFN2, OPA1, DRP1, MFF, NLRP3,caspase-1) were respectively detected by RT-PCR and Western Blot. The results were validated in TRPA1 shRNA and TRPV1 shRNA cells. In both cell types, 10% CSE increased intracellular and mitochondrial oxidative stress, induced Ca
IL-33 Expression Is Lower in Current Smokers at Both Transcriptomic and Protein Level
Publisher: American Thoracic Society
Date: 14-09-2023
EAACI guidelines on environmental science in allergic diseases and asthma – Leveraging artificial intelligence and machine learning to develop a causality model in exposomics
Publisher: Wiley
Date: 15-02-2023
DOI: 10.1111/ALL.15667
Abstract: Allergic diseases and asthma are intrinsically linked to the environment we live in and to patterns of exposure. The integrated approach to understanding the effects of exposures on the immune system includes the ongoing collection of large‐scale and complex data. This requires sophisticated methods to take full advantage of what this data can offer. Here we discuss the progress and further promise of applying artificial intelligence and machine‐learning approaches to help unlock the power of complex environmental data sets toward providing causality models of exposure and intervention. We discuss a range of relevant machine‐learning paradigms and models including the way such models are trained and validated together with ex les of machine learning applied to allergic disease in the context of specific environmental exposures as well as attempts to tie these environmental data streams to the full representative exposome. We also discuss the promise of artificial intelligence in personalized medicine and the methodological approaches to healthcare with the final AI to improve public health.
Molecular phenotypes of severe asthma
Publisher: European Respiratory Society
Date: 06-2019
Effects of Inhaled Corticosteroid Therapy on Expression and DNA-Binding Activity of Nuclear Factor κ B in Asthma
Publisher: American Thoracic Society
Date: 2000
DOI: 10.1164/AJRCCM.161.1.9809019
Abstract: We determined whether inhaled corticosteroid therapy modulates the expression of the transcription factor, nuclear factor kappa B (NF-kappaB), in patients with asthma. Fifteen stable patients with mild asthma underwent bronchoalveolar lavage (BAL) with bronchial biopsies in a double-blind, placebo-controlled and crossover study after placebo or after inhaled fluticasone propionate (500 microg twice daily). Fluticasone reduced the number of eosinophils in BAL fluid (BALF) and in airway biopsies, together with an improvement of bronchial responsiveness to methacholine. However, NF-kappaB DNA-binding in alveolar macrophages and in bronchial biopsies was not affected by fluticasone treatment. NF-kappaB expression was also measured by immunohistochemical staining with an antibody to the p65 component of NF-kappaB. Fluticasone caused an increase in the number of positive nuclear staining cells in the airway epithelium from 34. 1 +/- 5.0 to 64.1 +/- 8.0 per mm(2) (p = 0.002). In vitro studies of A549 epithelial cells stimulated by interleukin-1beta (IL-1beta) showed that dexamethasone increased p65 protein expression analyzed by Western blot. Despite an anti-inflammatory effect of fluticasone, there was no decrease in NF-kappaB-DNA binding and activation, indicating that this may not be a mechanism by which corticosteroids act in asthma. The significance of corticosteroid-induced increase in p65 protein expression is not known.
“T2-high” in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin
Publisher: European Respiratory Society (ERS)
Date: 21-12-2018
DOI: 10.1183/13993003.00938-2018
Abstract: Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild–moderate asthma into a T2-high phenotype. We examined whether currently available clinical biomarkers can predict AEC-defined T2-high phenotype within the U-BIOPRED cohort. The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from interleukin (IL)-13-exposed AECs. 37% of asthmatics (45% nonsmoking severe asthma, n=49 33% of smoking or ex-smoking severe asthma, n=18 and 28% mild–moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher exhaled nitric oxide fraction ( F eNO ) and blood and sputum eosinophils, but not serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. F eNO (≥30 ppb) and blood eosinophils (≥300 cells·µL −1 ) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression. T2-high severe asthma can be predicted to some extent from raised levels of F eNO , blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.
Ozone induction of cytokine‐induced neutrophil chemoattractant (CINC) and nuclear factor‐κb in rat lung: inhibition by corticosteroids
Publisher: Wiley
Date: 05-02-1996
DOI: 10.1016/0014-5793(95)01524-8
Abstract: We determined in rat lung whether ozone exposure was associated with the expression of the chemokine, cytokine-induced neutrophil chemoattractant (CINC), and of the transcription factor, NF-kappa B. CINC mRNA expression peaked at 2 h after cessation of ozone exposure, and returned to basal levels by 24 h. DNA-binding activity of NF-kappa B showed a marked increase after ozone, maximal at 2 h. Dexamethasone inhibited CINC mRNA and NF-kappa B expression, together with neutrophilic inflammation. Our data supports the concept that ozone leads to NF-kappa B activation which increases CINC mRNA expression. These series of events could lead to neutrophilic inflammation.
Differential regulation of the constitutive and inducible nitric oxide synthase mRNA by lipopolysacchride treatment in vivo in the rat
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1996
DOI: 10.1097/00003246-199607000-00026
Abstract: Endotoxin and cytokines have been reported to have both stimulatory and inhibitory effects on endothelial cell-derived nitric oxide release. The discrepancy may be explained by differential regulation of the endothelial and inducible type of nitric oxide synthase gene expression. This study aimed to investigate the differential effect of lipopolysaccharide treatment in vivo on the three isoforms (endothelial, brain-type, and inducible) of nitric oxide synthase gene expression in the rat. Prospective, controlled, animal trial. Experimental laboratory of a postgraduate medical research institution. Normal, anesthetized rats. Animals were treated with lipopolysaccharide (15 mg/kg iP), saline (1 mL/kg ip), or lipopolysaccharide plus dexamethasone (3 mg/kg ip, 50 mins before lipopolysaccharide administration) in vivo 4 hrs before experimentation. The expression of endothelial, brain-type, and inducible nitric oxide synthase mRNAs was quantified by Northern blot analysis using bovine, rat, and mouse cDNA probes, respectively. An endothelial nitric oxide synthase mRNA was detected at 4.3 kilobase in the heart, lung, and aorta, and a 10-kilobase brain-type nitric oxide synthase mRNA was detected in the brain. The endothelial and brain-type signals were strong in tissues from animals treated with saline, but were reduced by three- to four-fold in tissues from lipopolysaccharide-treated rats as estimated by optical density ratio. The 4.4-kilobase inducible nitric oxide synthase mRNA detected using the murine cDNA probe was absent or negligible in the heart, lung, and brain from saline-treated rats, but was markedly increased in the same tissues from lipopolysaccharide-treated animals. Dexamethasone significantly inhibited lipopolysaccharide-induced inducible nitric oxide synthase mRNA expression, but had no effect on the down-regulation of endothelial and brain nitric oxide synthase mRNAs. Rats treated with lipopolysaccharide in vivo display down-regulation of endothelial nitric oxide mRNA in the heart, lung, and aorta, and brain-type nitric oxide synthase mRNA in the brain There was a parallel up-regulation of inducible nitric oxide synthase mRNA in all tissues except in the aorta. Dexamethasone prevents the induction of inducible nitric oxide synthase mRNA. but has no effect on the down-regulation of endothelial and brain-type nitric oxide synthase mRNAs induced by lipopolysaccharide. Thus, endotoxin regulates constitutive and inducible nitric oxide synthase mRNA differentially.
P159 Peripheral Blood Mononuclear Cells from patients with Idiopathic Pulmonary Arterial Hypertension are Hyporesponsive to Inflammatory stimuli
Publisher: BMJ
Date: 14-11-2013
Investigating mitochondrial dysfunction in asthma
Publisher: European Respiratory Society
Date: 09-2015
Attenuated Production of Intracellular IL-10 and IL-12 in Monocytes from Patients with Severe Asthma
Publisher: Elsevier BV
Date: 03-2002
TLR7 promotes smoke-induced lung damage through the activity of mast cell tryptase
Publisher: Research Square Platform LLC
Date: 09-2020
DOI: 10.21203/RS.3.RS-57848/V2
Abstract: The authors have withdrawn this preprint due to erroneous posting.
Mapping a mouse model of severe asthma to human asthma using gene set variation analysis
Publisher: European Respiratory Society
Date: 09-2015
TLR7 promotes smoke-induced lung damage through the activity of mast cell tryptase
Publisher: Research Square Platform LLC
Date: 27-08-2020
DOI: 10.21203/RS.3.RS-57848/V1
Abstract: Toll-like receptor (TLR)7 is known for eliciting immunity against single-stranded RNA viruses. TLR7 was increased in both human and cigarette smoke (CS)-induced experimental chronic obstructive pulmonary disease (COPD). Severity of CS-induced emphysema and COPD was reduced in TLR7-deficient mice whilst inhalation of imiquimod (TLR7-agonist) induced emphysema in naïve mice. Imiquimod-induced emphysema was reduced in mice treated with mast cell stabilizer cromolyn or deficient in mast cell protease-6. Therapeutic treatment with anti-TLR7 monoclonal antibody suppressed CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells. We demonstrate an unexpected role for TLR7 in mediating emphysema and COPD through mast cell activity.
Th2 subsetting of U-BIOPRED asthma subjects based on airway transciptomic profiles
Publisher: European Respiratory Society
Date: 09-2015
Research highlights from the 2017 ERS International Congress: airway diseases in focus
Publisher: European Respiratory Society (ERS)
Date: 2018
DOI: 10.1183/23120541.00163-2017
Abstract: For another year, high-quality research studies from around the world transformed the annual ERS International Congress into a vivid platform to discuss trending research topics, to produce new research questions and to further push the boundaries of respiratory medicine and science. This article reviews only some of the high-quality research studies on asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and chronic cough that were presented during the congress through the Airway Diseases Assembly (ERS Assembly 5) and places them into the context of current knowledge and research challenges.
Systemic corticosteroid-associated serum analyte profiles in the U-BIOPRED severe asthma cohort
Publisher: European Respiratory Society
Date: 09-2015
Sputum supernatant profiling reveals inflammasome-associated signatures in severe asthmatics in U-BIOPRED
Publisher: European Respiratory Society
Date: 09-2015
Transcription Factors
Publisher: Elsevier
Date: 2022
Profile of fluticasone furoate/vilanterol dry powder inhaler combination therapy as a potential treatment for COPD
Publisher: Informa UK Limited
Date: 02-2014
DOI: 10.2147/COPD.S32604
I_MDS: an inflammatory bowel disease molecular activity score to classify patients with differing disease-driving pathways and therapeutic response to anti-TNF treatment
Publisher: Public Library of Science (PLoS)
Date: 30-04-2019
CpG‐ODN increases the release of VEGF in a mouse model of lung carcinoma
Publisher: Wiley
Date: 08-10-2010
DOI: 10.1002/IJC.25626
Abstract: Vascular endothelial-derived growth factor (VEGF) plays a fundamental role in the formation of new vessels within the tumour mass. Increasing evidence has highlighted the involvement of Toll-like receptors (TLRs) in cancer. Of interest, TLR9 is over-expressed in human lung carcinoma tissues. The aim of our study was to determine whether TLR9 activation could alter VEGF release in a mouse model of lung carcinoma. Lewis lung carcinoma cells were intravenously (i.v.) inoculated and 10 days later, tumour-bearing mice were treated with CpG-ODN (CpG, a TLR9 ligand) or PBS. CpG administration enhanced VEGF release, which was associated with increased tumour lesions in the lung. CpG induced high levels of IL-6 expression and activation of STAT3 in tumour-bearing mice. Moreover, CpG induced VEGF release from primary fibroblasts and endothelial cells, which correlated with IL-6 and TGFβ production. This may explain the large influx of fibroblasts and the production of basic fibroblast growth factor (bFGF) in the tumour mass. The administration of a monoclonal antibody against VEGF A arrested tumour progression and induced a Th1-like response in CpG-treated tumour-bearing mice. In conclusion, our study demonstrates that the combination of CpG with anti-VEGF monoclonal antibody could be of potential therapeutic in lung carcinoma.
Research highlights from the 2018 European Respiratory Society International Congress: airway disease
Publisher: European Respiratory Society (ERS)
Date: 02-2019
DOI: 10.1183/23120541.00225-2018
Abstract: The annual European Respiratory Society (ERS) International Congress (held in Paris in 2018) was once again a platform for discussion of the highest-quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses only some of the high-quality research studies presented at this year's Congress, with a particular focus on airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and cough, as presented through Assembly 5 of the ERS (Airway Diseases: Asthma and COPD). The authors establish the key take-home messages of these studies, compare their findings and place them in the context of current understanding.
Impaired innate immune gene profiling in airway smooth muscle cells from chronic cough patients
Publisher: Portland Press Ltd.
Date: 15-11-2017
DOI: 10.1042/BSR20171090
Abstract: Chronic cough is associated with airway inflammation and remodelling. Abnormal airway smooth muscle cell (ASMC) function may underlie mechanisms of chronic cough. Our objective was to examine the transcriptome and focused secretome of ASMCs from chronic cough patients and healthy non-cough volunteers. ASMC gene expression profiling was performed at baseline and/or after stimulation with polyinosinic:polycytidylic acid (poly(I:C)) to mimic viral infection. Supernatants were collected for multiplex analysis. Our results showed no significant differentially expressed genes (DEGs, false discovery rate (FDR) & .05) between chronic cough and healthy non-cough ASMCs at baseline. Poly(I:C) stimulation resulted in 212 DEGs (& .5 fold-change, FDR & .05) in ASMCs from chronic cough patients compared with 1674 DEGs in healthy non-cough volunteers. The top up-regulated genes included chemokine (C–X–C motif) ligand (CXCL) 11 (CXCL11), CXCL10, chemokine (C–C motif) ligand (CCL) 5 (CCL5) and interferon-induced protein 44 like (IFI44L) corresponding with inflammation and innate immune response pathways. ASMCs from cough subjects had enhanced activation of viral response pathways in response to poly(I:C) compared with healthy non-cough subjects, reduced activation of pathways involved in chronic inflammation and equivalent activation of neuroregulatory genes. The poly(I:C)-induced release of inflammatory mediators, including CXCL8, interleukin (IL)-6 and CXCL1, from ASMCs from cough patients was significantly impaired compared with healthy non-cough subjects. Addition of fluticasone propionate (FP) to poly(I:C)-treated ASMCs resulted in greater gene expression changes in healthy non-cough ASMCs. FP had a differential effect on poly(I:C)-induced mediator release between chronic cough and healthy non-cough volunteers. In conclusion, altered innate immune and inflammatory gene profiles within ASMCs, rather than infiltrating cells or nerves, may drive the cough response following respiratory viral infection.
Management of severe asthma: A European Respiratory Society/American Thoracic Society guideline,Лечение рекомендации и Американского тяжелой Европейского торакального бронхиальной респираторного общества астмы: общества
Publisher: Scientific and Practical Reviewed Journal Pulmonology
Date: 10-06-2021
DOI: 10.18093/0869-0189-2021-31-3-272-295
Abstract: This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including metaanalyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force’s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: • suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes • suggest using a blood eosinophil cut-point ≥150 μL −1 to guide anti-IL-5 initiation in adult patients with severe asthma • suggest considering specific eosinophil (≥260 μL −1 ) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy • suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4 – 5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies • suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype • suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.
Relationship between interleukin-13 and transferrin receptor-1 responses in the pathogenesis of asthma
Publisher: European Respiratory Society
Date: 04-09-2022
The pan janus kinase (JAK) inhibitor KN-002 suppresses inflammatory mediator release from severe asthma bronchial epithelial cells
Publisher: European Respiratory Society
Date: 05-09-2021
Pharmacist-led smoking cessation intervention in Australian primary care targeting smokers at risk of developing COPD
Publisher: Wiley
Date: 03-2018
DOI: 10.1111/RESP.13267
Epigenome-modifying tools in asthma
Publisher: Future Medicine Ltd
Date: 09-2015
DOI: 10.2217/EPI.15.53
Abstract: Asthma is a chronic disease which causes recurrent breathlessness affecting 300 million people worldwide of whom 250,000 die annually. The epigenome is a set of heritable modifications and tags that affect the genome without changing the intrinsic DNA sequence. These marks include DNA methylation, modifications to histone proteins around which DNA is wrapped and expression of noncoding RNA. Alterations in all of these processes have been reported in patients with asthma. In some cases these differences are linked to disease severity and susceptibility and may account for the limited value of genetic studies in asthma. Animal models of asthma suggest that epigenetic modifications and processes are linked to asthma and may be tractable targets for therapeutic intervention.
Montelukast inhibits tumour necrosis factor‐α‐mediated interleukin‐8 expression through inhibition of nuclear factor‐κB p65‐associated histone acetyltransferase activity
Publisher: Wiley
Date: 05-03-2008
DOI: 10.1111/J.1365-2222.2008.02963.X
Abstract: Montelukast is a potent cysteinyl leukotriene-1 receptor antagonist possessing some anti-inflammatory effects although the molecular mechanism of these anti-inflammatory effects is unknown. In this study, we aimed to investigate the effect of montelukast on nuclear factor (NF)-kappaB-associated histone acetylation activity in phorbol myristate acetate (PMA)-differentiated U937 cells. We examined the inhibitory effects of montelukast on TNF-alpha-induced IL-8 production in PMA-differentiated U-937 cells. U-937 cells were exposed to PMA (50 ng/mL) for 48 h to allow differentiation to macrophages. Macrophages were then exposed to TNF-alpha (10 ng/mL) in the presence or absence of montelukast (0.01-10 microm) for 24 h. After this time, the concentration of IL-8 in the culture supernatant was measured by sandwich-type ELISA kit. The effect of signalling pathways on TNF-alpha-induced IL-8 release was examined pharmacologically using selective NF-kappaB/IKK2 (AS602868, 3 microm), (PD98059, 10 microm) and p38 mitogen activated protein kinase (MAPK) (SB203580, 1 microm) inhibitors. NF-kappaB DNA binding activity was measured by a DNA-binding ELISA-based assay. NF-kappaB-p65-associated histone acetyltransferase (HAT) activity was measured by immunoprecipitation linked to commercial fluorescent HAT. TNF-alpha-induced IL-8 release was suppressed by an NF-kappaB inhibitor but not by MEK or p38 MAPK inhibitors. Montelukast induced a concentration-dependent inhibition of TNF-alpha-induced IL-8 release and mRNA expression that reached a plateau at 0.1 microm without affecting cell viability. Montelukast did not affect NF-kappaB p65 activation as measured by DNA binding but suppressed NF-kappaB p65-associated HAT activity. Montelukast inhibits TNF-alpha-stimulated IL-8 expression through changes in NF-kappaB p65-associated HAT activity. Drugs targeting these enzymes may enhance the anti-inflammatory actions of montelukast.
TRPV1 and TRPA1 in Lung Inflammation and Airway Hyperresponsiveness Induced by Fine Particulate Matter (PM2.5)
Publisher: Hindawi Limited
Date: 02-06-2019
DOI: 10.1155/2019/7450151
Abstract: Exposure to fine particulate matter (PM 2.5 ) has been associated with lung inflammation and airway hyperresponsiveness (AHR). Transient receptor potential (TRP) vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) both may play important roles in lung inflammation and AHR. We investigated whether PM 2.5 -induced lung inflammation and AHR could be prevented by blocking TRPV1 and TRPA1 channels. Mice were injected intraperitoneally with AMG9810 (30 mg/kg, a TRPV1 antagonist) or A967079 (30 mg/kg, a TRPA1 antagonist) or their combination or vehicle (PBS) one hour before intranasal instillation of PM 2.5 (7.8 mg/kg) or vehicle (PBS) for two consecutive days, and then the mice were studied 24 h later. All pretreatments inhibited PM 2.5 -induced AHR and inflammatory infiltration in the lung tissue and decreased inflammatory cytokine levels in the bronchoalveolar lavage fluid, together with oxidant levels in the lung. AMG9810 inhibited MFF expression and increased MFN2 expression while A967079 inhibited DRP1 expression and increased OPA1 expression combined pretreatment reduced MFF and DPR1 expression and increased MFN2 and OPA1 expression. All pretreatments inhibited the activation of the TLR4/NF- κ B pathway, while A967079 alone, and combined with AMG9810 also reduced the activation of the NLRP3/caspase-1 pathway. Both TRPV1 and TRPA1 channels play an important role in PM 2.5 -induced lung inflammation and AHR. However, inhibition of the TRPA1 channel or combined inhibition of TRPA1 and TRPV1 channels resulted in greater inhibitory effect on PM 2.5 -induced lung injury through regulating the mitochondrial fission/fusion proteins and inhibiting the TLR4/NF- κ B and NLRP3/caspase-1 pathways.
DEL ‐1, as an anti‐neutrophil transepithelial migration molecule, inhibits airway neutrophilic inflammation in asthma
Publisher: Wiley
Date: 08-09-2023
DOI: 10.1111/ALL.15882
Epigenetics and airways disease
Publisher: Springer Science and Business Media LLC
Date: 06-02-2006
Abstract: Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating ersity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease.
Phosphodiesterase expression in human epithelial cells
Publisher: American Physiological Society
Date: 10-1998
DOI: 10.1152/AJPLUNG.1998.275.4.L694
Abstract: Epithelial cells play a critical role in airway inflammation and have the capacity to produce many inflammatory mediators, including bioactive lipids and proinflammatory cytokines. Intracellular levels of cAMP and cGMP are important in the control of inflammatory cell function. These cyclic nucleotides are inactivated via a family of phosphodiesterase (PDE) enzymes, providing a possible site for drug intervention in chronic inflammatory conditions. We studied the expression of PDE activity in an epithelial cell line (A549) and in primary human airway epithelial cells (HAECs). We measured PDE function using specific inhibitors to identify the PDE families present and used RT-PCR to elucidate the expression of PDE isogenes. Both A549 cells and HAECs predominantly expressed PDE4 activity, with lesser PDE1, PDE3, and PDE5 activity. RT-PCR identified HSPDE4A5 and HSPDE4D3 together with HSPDE7. Inhibition of PDE4 and PDE3 reduced secretion by these cells. Epithelial PDE may be an important target for PDE4 inhibitors in the development of the control of asthmatic inflammation, particularly when delivered via the inhaled route.
Transcription Factors in Asthma
Publisher: Elsevier
Date: 1998
Inhibition of CD73 Improves B Cell-Mediated Anti-Tumor Immunity in a Mouse Model of Melanoma
Publisher: The American Association of Immunologists
Date: 09-2012
Abstract: CD73 is a cell surface enzyme that suppresses T cell-mediated immune responses by producing extracellular adenosine. Growing evidence suggests that targeting CD73 in cancer may be useful for an effective therapeutic outcome. In this study, we demonstrate that administration of a specific CD73 inhibitor, adenosine 5′-(α,β-methylene)diphosphate (APCP), to melanoma-bearing mice induced a significant tumor regression by promoting the release of Th1- and Th17-associated cytokines in the tumor microenvironment. CD8+ T cells were increased in melanoma tissue of APCP-treated mice. Accordingly, in nude mice APCP failed to reduce tumor growth. Importantly, we observed that after APCP administration, the presence of B cells in the melanoma tissue was greater than that observed in control mice. This was associated with production of IgG2b within the melanoma. Depletion of CD20+ B cells partially blocked the anti-tumor effect of APCP and significantly reduced the production of IgG2b induced by APCP, implying a critical role for B cells in the anti-tumor activity of APCP. Our results also suggest that APCP could influence B cell activity to produce IgG through IL-17A, which significantly increased in the tumor tissue of APCP-treated mice. In support of this, we found that in melanoma-bearing mice receiving anti–IL-17A mAb, the anti-tumor effect of APCP was ablated. This correlated with a reduced capacity of APCP-treated mice to mount an effective immune response against melanoma, as neutralization of this cytokine significantly affected both the CD8+ T cell- and B cell-mediated responses. In conclusion, we demonstrate that both T cells and B cells play a pivotal role in the APCP-induced anti-tumor immune response.
Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD
Publisher: BMJ
Date: 07-12-2022
DOI: 10.1136/THORAX-2021-217736
Abstract: Severe asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3). We examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity. Using gene set variation analysis, we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Differential gene expression and cellular convolution were used to define key regulated genes and cell types. Bronchial biopsies in patients with COPD at baseline showed a wide range of expression of the 3 TAC signatures. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-sequencing and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription correlated with the change in RV/TLC %predicted following 30-month ICS±LABA. Sputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of patients with COPD and identified a signature of airway mast cells as a predictor of corticosteroid responsiveness.
Cigarette smoke regulates the expression of TLR4 and IL-8 production by human macrophages
Publisher: Springer Science and Business Media LLC
Date: 05-2009
Abstract: Toll-like receptors (TLRs) are present on monocytes and alveolar macrophages that form the first line of defense against inhaled particles. The importance of those cells in the pathophysiology of chronic obstructive pulmonary disease (COPD) has well been documented. Cigarette smoke contains high concentration of oxidants which can stimulate immune cells to produce reactive oxygen species, cytokines and chemokines. In this study, we evaluated the effects of cigarette smoke medium (CSM) on TLR4 expression and interleukin (IL)-8 production by human macrophages investigating the involvement of ROS. TLR4 surface expression was downregulated on short term exposure (1 h) of CSM. The downregulation could be explained by internalization of the TLR4 and the upregulation by an increase in TLR4 mRNA. IL-8 mRNA and protein were also increased by CSM. CSM stimulation increased intracellular ROS-production and decreased glutathione (GSH) levels. The modulation of TLR4 mRNA and surface receptors expression, IRAK activation, IκB-α degradation, IL-8 mRNA and protein, GSH depletion and ROS production were all prevented by antioxidants such as N-acetyl-L-cysteine (NAC). TLR4 may be involved in the pathogenesis of lung emphysema and oxidative stress and seems to be a crucial contributor in lung inflammation.
Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts
Publisher: Wiley
Date: 07-06-2022
DOI: 10.1111/RESP.14302
Abstract: Severe asthma (SA) is a heterogeneous disease. Transcriptomic analysis contributes to the understanding of pathogenesis necessary for developing new therapies. We sought to identify and validate mechanistic pathways of SA across two independent cohorts. Transcriptomic profiles from U‐BIOPRED and Australian NOVocastrian Asthma cohorts were examined and grouped into SA, mild/moderate asthma (MMA) and healthy controls (HCs). Differentially expressed genes (DEGs), canonical pathways and gene sets were identified as central to SA mechanisms if they were significant across both cohorts in either endobronchial biopsies or induced sputum. Thirty‐six DEGs and four pathways were shared across cohorts linking to tissue remodelling/repair in biopsies of SA patients, including SUMOylation, NRF2 pathway and oxidative stress pathways. MMA presented a similar profile to HCs. Induced sputum demonstrated IL18R1 as a shared DEG in SA compared with healthy subjects. We identified enrichment of gene sets related to corticosteroid treatment immune‐related mechanisms activation of CD4 + T cells, mast cells and IL18R1 and airway remodelling in SA. Our results identified differentially expressed pathways that highlight the role of CD4 + T cells, mast cells and pathways linked to ongoing airway remodelling, such as IL18R1, SUMOylation and NRF2 pathways, as likely active mechanisms in the pathogenesis of SA.
Galactooligosaccharides and 2′-fucosyllactose can directly suppress growth of specific pathogenic microbes and affect phagocytosis of neutrophils
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.NUT.2022.111601
Abstract: Non-digestible oligosaccharides such as milk oligosaccharides (MOS) can regulate and influence immune function. As an ex le, galactooligosaccharides (GOS), and 2'-fucosyllactose (2'-FL a specific human MOS) regulate immune development and functionality. Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA), both serious pathogens, can cause severe and life-threatening infections. The aim of this study was to examine the effects of GOS and 2'-FL on bacterial growth and on polymorphonuclear (PMN) phagocytosis. PMNs were isolated from heparinized whole human blood before treatment/incubation with GOS (0.0625-10%), 2'-FL (0.5-2.5%) and/or GOS combined with 2'-FL (GOS 10%/2'-FL 2.5% GOS 0.0625%/2'-FL 0.5%) and incubation with green florescent protein (GFP)-labeled SA or PA for 60 h. GFP-relative fluorescent units (GFP-RFU) was measured ≤60 h using a plate reader. Bacterial lag time was determined by the time to onset of exponential bacterial fluorescence/growth alone or after co-culture of bacteria and PMN. Viable bacterial colony-forming units (CFUs) were determined after 60 h. SA and PA growth lag time was suppressed by co-incubation with GOS in a concentration-dependent manner. This was significant for both SA and PA at concentrations >2.5% GOS (P ≤ 0.05 for both SA and PA) but only for SA at 1% GOS (P ≤ 0.05). 1.5% 2'-FL significantly suppressed the lag time of SA growth (P ≤ 0.05) and was effective against SA and PA at 2.5% (P ≤ 0.01 and P ≤ 0.01, respectively). GOS (10%, 5%) and 2.5% 2'-FL significantly decreased SA and PA bacterial growth/CFUs (P ≤ 0.05). The data suggests that both GOS and 2'-FL can suppress growth of serious pathogens and enhance phagocytosis.
Exhaled carbon monoxide in asthmatics: a meta-analysis
Publisher: Springer Science and Business Media LLC
Date: 30-04-2010
Lung toxicity of particulates and gaseous pollutants using ex-vivo airway epithelial cell culture systems
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.ENVPOL.2022.119323
Abstract: Air pollution consists of a multi-faceted mix of gases and ambient particulate matter (PM) with erse organic and non-organic chemical components that contribute to increasing morbidity and mortality worldwide. In particular, epidemiological and clinical studies indicate that respiratory health is adversely affected by exposure to air pollution by both causing and worsening (exacerbating) diseases such as chronic obstructive pulmonary disease (COPD), asthma, interstitial pulmonary fibrosis and lung cancer. The molecular mechanisms of air pollution-induced pulmonary toxicity have been evaluated with regards to different types of PM of various sizes and concentrations with single and multiple exposures over different time periods. These data provide a plausible interrelationship between cellular toxicity and the activation of multiple biological processes including proinflammatory responses, oxidative stress, mitochondrial oxidative damage, autophagy, apoptosis, cell genotoxicity, cellular senescence and epithelial-mesenchymal transition. However, these molecular changes have been studied predominantly in cell lines rather than in primary bronchial or nasal cells from healthy subjects or those isolated from patients with airways disease. In addition, they have been conducted under different cell culture conditions and generally in submerged culture rather than the more relevant air-liquid interface culture and with a variety of air pollutant exposure protocols. Cell types may respond differentially to pollution delivered as an aerosol rather than being bathed in media containing agglomerations of particles. As a result, the actual pathophysiological pathways activated by different PMs in primary cells from the airways of healthy and asthmatic subjects remains unclear. This review summarises the literature on the different methodologies utilised in studying the impact of submicron-sized pollutants on cells derived from the respiratory tract with an emphasis on data obtained from primary human cell. We highlight the critical underlying molecular mechanisms that may be important in driving disease processes in response to air pollution in vivo.
Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA)
Publisher: European Respiratory Society (ERS)
Date: 13-10-2022
DOI: 10.1183/13993003.00606-2022
Abstract: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients’ and carers’ views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV 1 ) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.
Myeloid-derived suppressor cells in the blood of COVID-19 patients
Publisher: European Respiratory Society
Date: 05-09-2021
Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months
Publisher: Elsevier BV
Date: 2021
P189 Mitochondrial dysfunction in muscle and airway compartments in COPD: preliminary findings:
Publisher: BMJ
Date: 14-11-2013
The RNA binding proteins ZFP36L1 and ZFP36L2 are dysregulated in airway epithelium in human and a murine model of asthma
Publisher: Frontiers Media SA
Date: 19-10-2023
Asthma: NSAID Exacerbated Respiratory Disease (NERD) Formerly Aspirin-Intolerant Asthma
Publisher: Elsevier
Date: 2022
LATE-BREAKING ABSTRACT: Sputum transcriptome analysis yields eosinophilic and non-eosinophilic inflammatory mechanisms in UBIOPRED asthma cohort
Publisher: European Respiratory Society
Date: 09-2015
Cabbage and fermented vegetables: From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID‐19
Publisher: Wiley
Date: 15-09-2020
DOI: 10.1111/ALL.14549
Mesenchymal stem cells alleviate oxidative stress–induced mitochondrial dysfunction in the airways
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.JACI.2017.08.017
Abstract: Oxidative stress-induced mitochondrial dysfunction can contribute to inflammation and remodeling in patients with chronic obstructive pulmonary disease (COPD). Mesenchymal stem cells protect against lung damage in animal models of COPD. It is unknown whether these effects occur through attenuating mitochondrial dysfunction in airway cells. We sought to examine the effect of induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) on oxidative stress-induce mitochondrial dysfunction in human airway smooth muscle cells (ASMCs) in vitro and in mouse lungs in vivo. ASMCs were cocultured with iPSC-MSCs in the presence of cigarette smoke medium (CSM), and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), and apoptosis were measured. Conditioned medium from iPSC-MSCs and transwell cocultures were used to detect any paracrine effects. The effect of systemic injection of iPSC-MSCs on airway inflammation and hyperresponsiveness in ozone-exposed mice was also investigated. Coculture of iPSC-MSCs with ASMCs attenuated CSM-induced mitochondrial ROS, apoptosis, and ΔΨm loss in ASMCs. iPSC-MSC-conditioned medium or transwell cocultures with iPSC-MSCs reduced CSM-induced mitochondrial ROS but not ΔΨm or apoptosis in ASMCs. Mitochondrial transfer from iPSC-MSCs to ASMCs was observed after direct coculture and was enhanced by CSM. iPSC-MSCs attenuated ozone-induced mitochondrial dysfunction, airway hyperresponsiveness, and inflammation in mouse lungs. iPSC-MSCs offered protection against oxidative stress-induced mitochondrial dysfunction in human ASMCs and in mouse lungs while reducing airway inflammation and hyperresponsiveness. These effects are, at least in part, dependent on cell-cell contact, which allows for mitochondrial transfer, and paracrine regulation. Therefore iPSC-MSCs show promise as a therapy for oxidative stress-dependent lung diseases, such as COPD.
MIF antagonism restores corticosteroid sensitivity in a murine model of severe asthma
Publisher: European Respiratory Society
Date: 15-09-2018
Decision support system to evaluate VENTilation in the Acute Respiratory Distress Syndrome (DeVENT study) – Trial Protocol
Publisher: Cold Spring Harbor Laboratory
Date: 09-2021
DOI: 10.1101/2021.08.25.21262610
Abstract: The Acute Respiratory Distress Syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the in idual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using in idual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS. We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS. Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic), could change the outcome of mechanically ventilated patients during the course of this and future pandemics. ClinicalTrials.gov identifier ( NCT number): NCT04115709 Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see eporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/ ).
Cellular endotoxin desensitization in patients with severe chronic heart failure
Publisher: Wiley
Date: 08-2005
DOI: 10.1016/J.EJHEART.2004.09.014
Abstract: Increased levels of bacterial lipopolysaccharide (LPS) have been demonstrated in chronic heart failure (CHF). LPS can induce cellular desensitization, with specific down-regulation of LPS-mediated cellular tumor necrosis factor (TNF-alpha) production which does not affect other cytokine parameters. It is not known if LPS desensitization occurs in CHF. Mononuclear cells from 24 CHF patients (mean age 70+/-2 years, age range 58 to 78 years, NYHA class 3.0+/-0.2) and 11 healthy controls (mean age 53+/-3 years, age range 39 to 75 years) were separated from venous blood and cultured for 24 h with LPS (E. coli, 0-10 ng/mL). Culture supernatants were tested for TNF-alpha and interleukin-1 receptor antagonist (IL-1RA). Patients were subgrouped into mild (n=10), moderate (n=5), and severe (n=9) CHF. Independently of age, mononuclear cells from patients with severe heart failure produced less TNF-alpha than controls (p<0.05) and patients with mild (p<0.001) or moderate CHF (p<0.05). IL-1RA release was higher for CHF patients as a group, compared with controls (p<0.05). There was no significant difference in IL-1RA release between CHF patient subgroups. Mononuclear cells from patients with severe heart failure produce significantly less TNF-alpha than healthy controls or patients with mild to moderate disease. Production of IL-1RA is not affected. This resembles a picture indicative of LPS desensitization occurring in patients with severe CHF.
Expression of eosinophil-associated gene signatures in U-BIOPRED severe asthma
Publisher: European Respiratory Society
Date: 04-09-2022
Whole blood endotoxin responsiveness in patients with chronic heart failure: the importance of serum lipoproteins
Publisher: Wiley
Date: 28-05-2005
DOI: 10.1016/J.EJHEART.2004.09.013
Abstract: Endotoxin [lipopolysaccharide (LPS)] may be an important stimulus for cytokine release in patients with chronic heart failure (CHF). We sought to investigate the relationship between whole blood endotoxin responsiveness and serum lipoprotein concentrations. It is not known if low-dose LPS is sufficient to stimulate immune activation. Whole blood from 32 CHF patients (mean age 66+/-2 years, NYHA class 2.7+/-0.2, five female) and 11 healthy control subjects (mean age 47+/-4 years, six female) was stimulated with LPS at nine different concentrations (0.001 to 10 ng/mL), and tumor necrosis factor (TNF-alpha) release was quantified. Reference standard endotoxin at concentrations of 0, 0.6, 1, and 3 EU/ml was added to whole blood from nine CHF patients (age 64+/-9.1 years, all NYHA class II, eight male) and incubated for 6 h, the TNF-alpha production being measured. Serum lipoproteins were quantified using standard techniques. In CHF patients, there was an inverse relationship between whole blood TNF-alpha release and serum cholesterol which was strongest at 0.6 ng/mL of LPS (r=-0.53, p=0.002). A similar although weaker relationship was found for serum HDL. No such correlation was found in healthy subjects or with serum LDL (all r(2)<0.1). Low concentrations of LPS induced a stepwise increase in TNF-alpha release from whole blood to concentrations well above those seen in CHF. Serum lipoproteins may play an important role in regulating LPS bioactivity in CHF. Very low LPS activity, at levels seen in vivo in CHF, can induce significant TNF-alpha production ex vivo.
Steroid resistance in asthma: Mechanisms and treatment options
Publisher: Springer Science and Business Media LLC
Date: 04-2008
DOI: 10.1007/S11882-008-0028-4
Abstract: Glucocorticoid insensitivity presents a profound management problem in patients with asthma because conventional therapies are not effective. Glucocorticoids, acting through the glucocorticoid receptor (GR), are able to selectively repress inflammatory gene expression by utilizing several distinct mechanisms targeting nuclear factor-varphiB and activator protein-1 activation complexes and by effects on mitogen-activated protein kinases. Different model systems often activate distinct sets of signaling molecules and different glucocorticoid responsiveness may result from differences in concentrations and timing of steroid treatment of cells, GR expression levels, and the precise inflammatory stimulus used. Thus, abnormal activation of many signaling pathways may affect corticosteroid responsiveness in patients with corticosteroid-resistant asthma. Understanding the molecular mechanisms of GR action and inaction may lead to the development of new anti-inflammatory drugs or enable clinicians to reverse the relative steroid-insensitivity that is characteristic of some patients with severe asthma.
Discordant use of short‐acting β2 agonists in children and adults with severe, uncontrolled asthma from the U‐BIOPRED cohort
Publisher: Wiley
Date: 24-11-2020
DOI: 10.1002/PPUL.25171
Sputum macrophage diversity and activation in asthma: Role of severity and inflammatory phenotype
Publisher: Wiley
Date: 17-08-2020
DOI: 10.1111/ALL.14535
Correction: Suppression of GATA-3 Nuclear Import and Phosphorylation: A Novel Mechanism of Corticosteroid Action in Allergic Disease
Publisher: Public Library of Science (PLoS)
Date: 07-09-2018
Erratum to: Building bridges for innovation in ageing: Synergies between action groups of the EIP on AHA
Publisher: Springer Science and Business Media LLC
Date: 23-11-2016
Coordinated regulation of IL-4 and IL-13 expression in human T cells: 3C analysis for DNA looping
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.BBRC.2011.12.069
Abstract: Asthma is a chronic allergic disorder characterised by chronic inflammation. The balance of type I and type II (CD4+) T helper cells is of critical importance. In asthma there is an overexpression of T(H)2 cytokines, such as IL-4, IL-5 and IL-13. The genes encoding these cytokines are located together the same chromosomal region, 5q31.1 in humans. Here we confirm a central role for the transcription factors NFAT and GATA3 in the regulation of human IL-4 and IL-13. Chromatin Conformation Capture (3C) demonstrated the formation of specific ligation products containing spliced IL-4 and IL-13 DNA sequences in human T(H)2 polarised HuT-78 cells. This suggests that co-ordinate expression of T(H)2 cytokines, under the control of GATA3 and NFAT1 is due to the formation of a chromatin hub by DNA looping.
Decreased Serum Levels of Angiotensin Converting Enzyme (ACE)2 and Enhanced Cytokine Levels with Severity of COVID-19: Normalisation Upon Disease Recovery
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3961252
Is diet partly responsible for differences in COVID-19 death rates between and within countries?
Publisher: Wiley
Date: 27-05-2020
DOI: 10.1186/S13601-020-00323-0
Abstract: Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit.
S112 HDAC activity in macrophages in experimental rhinovirus infection in COPD
Publisher: BMJ
Date: 14-11-2013
255 Microarray Analysis Maps Global Effects of Epigenetic Bromodomain Inhibitor JQ1 on Gene Expression in Transforming Growth Factor-β-Stimulated Adult Lung Fibroblasts
Publisher: Oxford University Press (OUP)
Date: 24-04-2016
TGF-β Signaling Pathways in Different Compartments of the Lower Airways of Patients With Stable COPD
Publisher: Elsevier BV
Date: 04-2018
Role of microRNAs in allergic asthma
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
Metabolic re-patterning in COPD airway smooth muscle cells
Publisher: European Respiratory Society (ERS)
Date: 11-2017
DOI: 10.1183/13993003.00202-2017
Abstract: Chronic obstructive pulmonary disease (COPD) airways are characterised by thickening of airway smooth muscle, partly due to airway smooth muscle cell (ASMC) hyperplasia. Metabolic reprogramming involving increased glycolysis and glutamine catabolism supports the biosynthetic and redox balance required for cellular growth. We examined whether COPD ASMCs show a distinct metabolic phenotype that may contribute to increased growth. We performed an exploratory intracellular metabolic profile analysis of ASMCs from healthy nonsmokers, healthy smokers and COPD patients, under unstimulated or growth conditions of transforming growth factor (TGF)-β and fetal bovine serum (FBS). COPD ASMCs showed impaired energy balance and accumulation of the glycolytic product lactate, glutamine, fatty acids and amino acids compared to controls in unstimulated and growth conditions. Fatty acid oxidation capacity was reduced under unstimulated conditions. TGF-β/FBS-stimulated COPD ASMCs showed restoration of fatty acid oxidation capacity, upregulation of the pentose phosphate pathway product ribose-5-phosphate and of nucleotide biosynthesis intermediates, and increased levels of the glutamine catabolite glutamate. In addition, TGF-β/FBS-stimulated COPD ASMCs showed a higher reduced-to-oxidised glutathione ratio and lower mitochondrial oxidant levels. Inhibition of glycolysis and glutamine depletion attenuated TGF-β/FBS-stimulated growth of COPD ASMCs. Changes in glycolysis, glutamine and fatty acid metabolism may lead to increased biosynthesis and redox balance, supporting COPD ASMC growth.
Phenotyping asthma with airflow obstruction in middle-aged and older adults: a CADSET clinical research collaboration
Publisher: BMJ
Date: 08-2023
DOI: 10.1136/BMJRESP-2023-001760
Abstract: The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts. This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV 1 /FVC .7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model. The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts ( cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1.68 (95% CI 1.06 to 2.68)) than COPD-only, independent of age, sex, smoking status and BMI. AO is a relatively prevalent respiratory phenotype associated with more dyspnoea and a higher risk of coronary artery disease and elevated blood eosinophil counts in the general population compared with both asthma-only and COPD-only.
Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma
Publisher: Springer Science and Business Media LLC
Date: 18-05-2003
DOI: 10.1038/NG1166
Histone Acetylase and Deacetylase Activity in Alveolar Macrophages and Blood Mononocytes in Asthma
Publisher: American Thoracic Society
Date: 15-07-2004
Changes in PD-1- and CTLA-4-bearing Blood Lymphocytes in ICU COVID-19 Patients Treated with Favipiravir/Kaletra or Dexamethasone/Remdesivir: A Pilot Study
Publisher: Knowledge E DMCC
Date: 25-02-2023
DOI: 10.18502/IJAAI.V22I1.12012
Abstract: COVID-19, caused by SARS-CoV-2, requires new approaches to control the disease. Programmed cell death protein (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) play important roles in T-cell exhaustion in severe COVID-19. This study evaluated the frequency of whole blood lymphocytes expressing PD-1 and CTLA-4 in COVID-19 patients upon admission to the intensive care unit (ICU) (i.e., severe) or infection ward (i.e., moderate) and after 7 days of antiviral therapy. COVID-19 patients were treated with either favipiravir or Kaletra (FK group, 11 severe and 11 moderate) or dexamethasone plus remdesivir (DR group, 7 severe and 10 moderate) for 7 days in a pilot study. Eight healthy control subjects were also enrolled. The frequency of PD-1+ and CTLA-4+ lymphocytes in whole blood was evaluated by flow cytometry. Patients on DR therapy had shorter hospital stays than those on FK therapy. The frequency of PD-1+ lymphocytes in the FK group at baseline differed between COVID-19 patients and healthy controls, while the frequency of both PD-1+ and CTLA-4+ cells increased significantly 7 days of FK therapy. The response was similar in both moderate and severe patients. In contrast,the frequency of PD-1+ and CTLA-4+ lymphocytes varied significantly between patients and healthy controls before DR treatment. DR therapy enhanced PD-1+ but not the CTLA-4+ frequency of these cells after 7 days. We show that the frequency of PD-1 and CTAL-4-bearing lymphocytes during hospitalization was increased in Iranian ICU COVID-19 patients who received FK treatment, but that the frequency of CTLA-4+ cells was higher at baseline and did not increase in patients who received DR. The effectiveness of DR treatment may reflect differences in T-cell activation or exhaustion status, particularly in CTLA-4-expressing cells.
Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease
Publisher: Wiley
Date: 20-10-2004
DOI: 10.1111/J.1365-2559.2004.01952.X
Abstract: To study the expression of mucins in peripheral airways in patients with chronic obstructive pulmonary disease (COPD). Peripheral lung sections from smokers with COPD (n = 9) and age-matched controls including smokers (n = 11) and lifelong non-smokers with normal lung function (n = 6) were stained with alcian blue, periodic acid-Schiff (PAS) and by immunohistochemistry of mucins (MUC): MUC2, MUC4, MUC5AC, MUC5B and MUC6. Histochemical staining and immunoreactivity of bronchiolar epithelium were graded and the presence or absence of stained mucus in the bronchiolar lumen was evaluated. There were no differences in alcian blue and PAS epithelial staining between the three groups. Intraluminal PAS staining was significantly more frequent among COPD subjects (P < 0.05). The expression of MUC5AC was significantly higher in the bronchiolar epithelium of patients with COPD (P < 0.05). Within the bronchiolar lumen, the predominant mucin was MUC5B. Intraluminal MUC5B was significantly more frequent among COPD patients (P < 0.05). COPD is specifically associated with increased expression of MUC5B in the bronchiolar lumen and of the mucin MUC5AC in the bronchiolar epithelium. These changes in mucin production in the peripheral airways may contribute to the pathophysiology of COPD.
Systems Biology in Asthma
Publisher: Springer International Publishing
Date: 2023
MMP10andMETas predictive classifiers of bronchial eosinophilic asthma in UBIOPRED
Publisher: European Respiratory Society
Date: 09-2015
ERS International Congress, Madrid, 2019: highlights from the Airway Diseases, Asthma and COPD Assembly
Publisher: European Respiratory Society (ERS)
Date: 2020
DOI: 10.1183/23120541.00341-2019
Abstract: The European Respiratory Society (ERS) International Congress 2019 in Madrid, Spain, was a platform for scientific discussion of the highest quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses some of the high-quality research studies presented at that Congress, with a focus on airway diseases, including asthma, COPD, small airways, bronchiectasis and cough, presented through the Airway Diseases, Asthma and COPD Assembly (Assembly 5) of the ERS. The authors establish the key take-home messages of these studies, compare their findings and place them into context of current understanding.
Expression of Heme Oxygenase Isoenzymes 1 and 2 in Normal and Asthmatic Airways
Publisher: American Thoracic Society
Date: 11-2000
DOI: 10.1164/AJRCCM.162.5.9909081
Abstract: Heme oxygenase (HO) is considered to be an antioxidant enzyme that catabolizes heme to produce carbon monoxide (CO) and biliverdin. We determined the expression and distribution of HO-1 and HO-2, two isoenzymes of HO, in the airways of patients with asthma, and determined the effect of inhaled corticosteroid therapy. Immunostaining for both enzymes was widely distributed in the airways' submucosa, particularly in airway epithelium and submucosal macrophages (CD68(+)) as determined by double immunostaining. There was no difference in intensity and extent of staining in biopsies from normal subjects (n = 10) and subjects with asthma (n = 10). Following 1 mo of treatment with inhaled corticosteroids (budesonide 1,600 microg/d), there was no significant change in the expression and distribution of either HO-1 or HO-2 in the airways' submucosa in eight subjects with mild asthma, despite a significant reduction in airway eosinophils and a reduction in bronchial responsiveness to methacholine. Levels of exhaled nitric oxide were significantly reduced, but exhaled CO levels remained unchanged by the treatment. Treatment with a placebo inhaler (n = 8) had no effects on these parameters. Thus, both HO-1 and HO-2 are extensively distributed equally in normal subjects and subjects with asthma, and are not modulated by inhaled corticosteroid therapy in subjects with asthma. HO may be an important endogenous antioxidant enzyme.
Pathophysiology of severe asthma
Publisher: European Respiratory Society
Date: 06-2019
Characteristics of fine and ultrafine aerosols in the London underground
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.SCITOTENV.2022.159315
Abstract: Underground railway systems are recognised spaces of increased personal pollution exposure. We studied the number-size distribution and physico-chemical characteristics of ultrafine (PM
Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase
Publisher: Elsevier BV
Date: 02-2004
Clinical phenotypes of asthma should link up with disease mechanisms
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
Late Breaking Abstract - Longitudinal analysis of variation in clinical features from the U-BIOPRED severe asthma cohort
Publisher: European Respiratory Society
Date: 15-09-2018
eNose breath prints as a surrogate biomarker for classifying patients with asthma by atopy
Publisher: Elsevier BV
Date: 11-2020
SARS-CoV2 in public spaces in West London, UK during COVID-19 pandemic
Publisher: BMJ
Date: 05-2023
DOI: 10.1136/BMJRESP-2022-001574
Abstract: Spread of SARS-CoV2 by aerosol is considered an important mode of transmission over distances m, particularly indoors. We determined whether SARS-CoV2 could be detected in the air of enclosed/semi-enclosed public spaces. Between March 2021 and December 2021 during the easing of COVID-19 pandemic restrictions after a period of lockdown, we used total suspended and size-segregated particulate matter (PM) s lers for the detection of SARS-CoV2 in hospitals wards and waiting areas, on public transport, in a university c us and in a primary school in West London. We collected 207 s les, of which 20 (9.7%) were positive for SARS-CoV2 using quantitative PCR. Positive s les were collected from hospital patient waiting areas, from hospital wards treating patients with COVID-19 using stationary s lers and from train carriages in London underground using personal s lers. Mean virus concentrations varied between 429 500 copies/m 3 in the hospital emergency waiting area and the more frequent 164 000 copies/m 3 found in other areas. There were more frequent positive s les from PM s lers in the PM2.5 fractions compared with PM10 and PM1. Culture on Vero cells of all collected s les gave negative results. During a period of partial opening during the COVID-19 pandemic in London, we detected SARS-CoV2 RNA in the air of hospital waiting areas and wards and of London Underground train carriage. More research is needed to determine the transmission potential of SARS-CoV2 detected in the air.
Tumour Necrosis Factor-α Regulates Human Eosinophil Apoptosis via Ligation of TNF-Receptor 1 and Balance between NF-κB and AP-1
Publisher: Public Library of Science (PLoS)
Date: 28-02-2014
Ezrin, a membrane cytoskeleton cross linker protein, as a marker of epithelial damage in asthma
Publisher: European Respiratory Society
Date: 15-09-2018
U-BIOPRED accessible handprint: combining omics platforms to identify stable asthma subphenotypes
Publisher: European Respiratory Society
Date: 15-09-2018
Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
Publisher: European Respiratory Society (ERS)
Date: 04-11-2021
DOI: 10.1183/13993003.00142-2021
Abstract: Asthma phenotyping requires novel biomarker discovery. To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to s les from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.
Effects of dexamethasone and anti-inflammatory drugs on inflammatory cytokines from bronchial epithelial cells of COPD patients
Publisher: European Respiratory Society
Date: 09-2015
Transcriptomic analysis of cellular senescence signatures in severe asthma
Publisher: European Respiratory Society
Date: 04-09-2022
A novel transcription factor inhibitor, SP100030, inhibits cytokine gene expression, but not airway eosinophilia or hyperresponsiveness in sensitized and allergen‐exposed rat
Publisher: Wiley
Date: 11-2001
Effects of glucocorticoids on gene transcription
Publisher: Elsevier BV
Date: 10-2004
DOI: 10.1016/J.EJPHAR.2004.07.011
Abstract: Glucocorticoids bind to and activate a cytoplasmic glucocorticoid receptor. The activated glucocorticoid receptor translocates into the nucleus and binds to specific response elements in the promoter regions of anti-inflammatory genes such as lipocortin-1 and secretory leukocyte protease inhibitor (SLPI). However, the major anti-inflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), that mediate the expression of inflammatory genes. NF-kappaB switches on inflammatory genes via a process involving recruitment of transcriptional co-activator proteins and changes in chromatin modifications such as histone acetylation. This process must occur in the correct temporal manner to allow for effective inflammatory gene expression to occur. The interactions between NF-kappaB and the glucocorticoid receptor result in differing effects on histone modifications and chromatin remodelling. Drugs that enhance glucocorticoid receptor nuclear translocation (long acting beta-agonists) and GR-associated histone deacetylases activity (theophylline) have been shown to be effective add-on therapies. In addition, dissociated glucocorticoids that target NF-kappaB preferentially have also been successful in the treatment of allergic disease.
Potential role of c-Jun NH2-terminal kinase in allergic airway inflammation and remodelling: effects of SP600125
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.EJPHAR.2004.11.040
Abstract: Asthma is a chronic inflammatory disease of the airways associated with structural changes such as increased airway smooth muscle mass, which may contribute to impairment of lung function. To determine whether c-Jun NH2-terminal kinase (JNK) of the mitogen-activated protein kinase signalling pathway participated in these changes, the effects of an inhibitor, SP600125 (anthra [1, 9-cd] pyrazole-6 (2H)-one), were examined in a murine model of chronic airway inflammation and remodelling. Mice sensitised to ovalbumin were exposed to ovalbumin aerosol and were treated with SP600125 [30 mg kg(-1) intraperitoneal (i.p.)] on days of exposure. SP600125 significantly reduced eosinophil and lymphocyte numbers in bronchoalveolar lavage fluid, suppressed eosinophilic inflammation within the bronchial submucosa, inhibited goblet cell hyperplasia, and increased airway smooth muscle cell number in allergen-exposed mice. SP600125 also inhibited allergen-induced increase in bronchial responsiveness. SP600125 inhibited JNK activity in the challenged lungs. Although SP 600125 may also have other effects, we conclude that c-Jun NH2-terminal kinase may play a role in allergen-induced inflammation and remodelling associated with bronchial hyperresponsiveness.
Steroid Resistance in Asthma: Molecular Mechanisms
Publisher: American Thoracic Society
Date: 08-1996
DOI: 10.1164/AJRCCM/154.2_PT_2.S58
Abstract: Biochar is widely used to remove hexavalent chromium [Cr(VI)] from wastewater through adsorption, which is recognized as a facile, cost-efficient, and high-selectivity approach. In this study, a versatile strategy that combines delignification with subsequent carbonization and KOH activation is proposed to prepare a novel woody biochar from waste poplar sawdust. By virtue of the unique multilayered and honeycomb porous structure induced by delignification and activation processes, the resultant activated carbonized delignified wood (ACDW) exhibits a high specific surface area of 970.52 m
Bromodomain and Extraterminal Proteins Suppress NF-E2–Related Factor 2–Mediated Antioxidant Gene Expression
Publisher: The American Association of Immunologists
Date: 15-05-2014
Abstract: Oxidative stress, a pathogenetic factor in many conditions, including chronic obstructive pulmonary disease, arises due to accumulation of reactive oxygen species and defective antioxidant defenses in the lungs. The latter is due, at least in part, to impaired activation of NF-E2–related factor 2 (Nrf2), a transcription factor involved in the activation of antioxidant and cytoprotective genes. The bromodomain and extraterminal (BET) proteins, Brd2, Brd3, Brd4, and BrdT, bind to acetylated lysine residues on histone or nonhistone proteins recruiting transcriptional regulators and thus activating or repressing gene transcription. We investigated whether BET proteins modulate the regulation of Nrf2-dependent gene expression in primary human airway smooth muscle cells and the human monocytic cell line, THP-1. Inhibition of BET protein bromodomains using the inhibitor JQ1+ or attenuation of Brd2 and Brd4 expression using small interfering RNA led to activation of Nrf2-dependent transcription and expression of the antioxidant proteins heme oxygenase-1, NADPH quinone oxidoreductase 1, and glutamate-cysteine ligase catalytic subunit. Also, JQ1+ prevented H2O2-induced intracellular reactive oxygen species production. By coimmunoprecipitation, BET proteins were found to be complexed with Nrf2, whereas chromatin–immunoprecipitation studies indicated recruitment of Brd2 and Brd4 to Nrf2-binding sites on the promoters of heme oxygenase-1 and NADPH quinone oxidoreductase 1. BET proteins, particularly Brd2 and Brd4, may play a key role in the regulation of Nrf2-dependent antioxidant gene transcription and are hence an important target for augmenting antioxidant responses in oxidative stress–mediated diseases.
Systematic review of lung function and COPD with peripheral blood DNA methylation in population based studies
Publisher: Springer Science and Business Media LLC
Date: 20-03-2017
Cigarette Smoke Induced Airway Inflammation Is Independent of NF-κB Signalling
Publisher: Public Library of Science (PLoS)
Date: 22-01-2013
Functional effects of the microbiota in chronic respiratory disease
Publisher: Elsevier BV
Date: 10-2019
Salmeterol with fluticasone enhances the suppression of IL-8 release and increases the translocation of glucocorticoid receptor by human neutrophils stimulated with cigarette smoke
Publisher: Springer Science and Business Media LLC
Date: 04-07-2008
Modulation of ozone-induced airway hyperresponsiveness and inflammation by interleukin-13
Publisher: European Respiratory Society (ERS)
Date: 09-2008
DOI: 10.1183/09031936.00121607
Abstract: The present study aimed to determine whether the T-helper cell type 2-derived cytokines, interleukin (IL)-4 and -13, can modulate the lung response to ozone exposure. IL-13(-/-), IL-4/13(-/-) and IL-13-overexpressing transgenic (Tg) mice were exposed to ozone (3 ppm 3 h) or air. Wild-type (Wt) Balb/c mice and transgenic-negative littermates (IL-13Wt) were used as controls for gene-deficient and IL-13Tg mice, respectively. IL-4/13(-/-) and IL-13(-/-) mice developed a lesser degree of ozone-induced airway hyperresponsiveness (AHR) while IL-13Tg mice developed a greater degree of AHR compared with ozone-exposed wild-type or IL-13Wt mice, respectively. Ozone caused a time-dependent increase of bronchoalveolar lavage (BAL) neutrophils and macrophages in wild-type mice, maximal at 20-24 h, which was attenuated in the IL-13(-/-) and IL-4/13(-/-) mice. In IL-13Tg mice, there was a greater increase in BAL neutrophils after ozone exposure compared with IL-13Wt mice. Using quantitative real-time PCR, ozone-induced mRNA expression for IL-6 and keratinocyte chemokine was further enhanced in IL-13(-/-) and IL-4/13(-/-) mice, and was inhibited in IL-13Tg mice. Macrophage inflammatory protein (MIP)-3alpha/CCL20 expression was enhanced after ozone exposure in wild-type mice, inhibited in IL-13(-/-) and IL-4/13(-/-) mice, while in IL-13Tg mice it was enhanced. A similar pattern of expression was observed with lipopolysaccharide-induced cytokine (LIX/CXCL5/ENA-78) expression. In conclusion, interleukin-13 augments ozone-induced airway hyperresponsiveness and neutrophilic inflammation, possibly through modulation of certain cytokines induced by ozone exposure.
Histone acetylation and deacetylation: importance in inflammatory lung diseases
Publisher: European Respiratory Society (ERS)
Date: 03-2005
DOI: 10.1183/09031936.05.00117504
Abstract: Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappa B. Gene expression is regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein, with intrinsic histone acetyltransferase (HAT) activity. Conversely, gene repression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT activity and some reduction in HDAC activity, which is restored by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through the inhibition of HAT activity and by the recruitment of HDAC2 to the activated inflammatory gene complex. In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the lified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen with latent adenovirus infections. The reduction in histone deacetylase activity can be restored by theophylline, which may be able to reverse steroid resistance in chronic obstructive pulmonary disease and other inflammatory diseases.
Plasma protein profiles as markers of asthma severity and exposure to oral corticosteroids in U-BIOPRED and BIOAIR
Publisher: European Respiratory Society
Date: 07-09-2020
DNA methylation modules in airway smooth muscle are associated with asthma severity
Publisher: European Respiratory Society (ERS)
Date: 15-02-2018
Cytokine induction of cytosolic phospholipase A2 and cyclooxygenase-2 mRNA is suppressed by glucocorticoids in human epithelial cells
Publisher: Elsevier BV
Date: 11-1996
DOI: 10.1016/S0024-3205(96)00590-5
Abstract: Prostaglandin (PG) release, which is increased in vivo by inflammatory conditions and in vitro by pro-inflammatory cytokines, is decreased by glucocorticoids. Two phospholipase A2 isoforms, secretory (sPLA2) and cytosolic (cPLA2,), have been implicated in inflammation. These enzymes catalyse the release of arachidonic acid which is then converted to prostaglandins by the cyclooxygenases (COX-1 and COX-2). Regulation of these events at the mRNA level is poorly characterised in epithelial cells. We have used a human epithelial-like cell line (A549) as a model system to study mRNA expression of sPLA2, cPLA2, COX-1 and COX-2. Following treatment of cells and extraction of RNA, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to examine expression of these genes. We show a coordinate induction of both cPLA2 and COX-2 mRNA by pro-inflammatory cytokines which correlated with increased PGE2 release. By contrast, sPLA2 mRNA was undetectable and COX-1 was found to be expressed at a constant low level. In addition dexamethasone pretreatment significantly reduced both cPLA2 and COX-2 mRNA levels as well as PGE2 release following cytokine stimulation. These data indicate a major role for control of prostaglandin synthesis at the mRNA level of key synthetic genes in epithelial cells. Furthermore we show that a major mechanism of glucocorticoid action in preventing prostaglandin release occurs by suppression of cPLA2 and COX-2 mRNA levels.
Superinduction of COX‐2 mRNA by cycloheximide and interleukin‐1β involves increased transcription and correlates with increased NF‐κB and JNK activation
Publisher: Wiley
Date: 24-11-1997
DOI: 10.1016/S0014-5793(97)01362-8
Abstract: Many primary response genes, including cyclooxygenase-2 (COX-2), exhibit mRNA superinduction following agonist stimulation in the presence of translational blockers such as cycloheximide. This is widely assumed to result from mRNA stabilisation. However, superinduction of IL-1beta-induced COX-2 mRNA levels by cycloheximide in pulmonary type II A549 cells occurred by increased transcription and not by mRNA stabilisation. Furthermore, equivalent effects were observed on NF-kappaB binding to COX-2 promoter kappaB sites and activation of the Jun N-terminal kinases (JNK), p54 and p46. These signalling pathways play important roles in COX-2 induction and may therefore account for the observed increases in COX-2 transcription. These data are consistent with negative feed-back involving down-regulation of NF-kappaB by de novo IkappaB alpha synthesis and suggest that JNK activation may also be down-regulated by a cycloheximide sensitive process.
Asthma: Application of Cell and Molecular Biology Techniques to Unravel Causes and Pathophysiological Mechanisms
Publisher: Humana Press
Date: 2000
Abstract: The condition termed "asthma" has been difficult to define satisfactorily. Much of this problem arises from poor understanding of its causes, natural history, and pathophysiology, and also from a lack of a specific marker(s) of the disease. To the clinician, the diagnosis of asthma is not difficult in most cases, particularly if patients present early with symptoms of intermittent wheeze and chest tightness, and if their symptoms respond to particular treatments, such as β-adrenergic agonists. Early definitions of asthma included the presence of airway obstruction that could spontaneously reverse with treatment, and also the increased narrowing of the airways to non-specific bronchoconstrictor stimuli, i.e., bronchial hyperresponsiveness (BHR). The essential elements of this definition were useful in separating asthma from other conditions, such as chronic bronchitis, chronic obstructive pulmonary disease, and emphysema, which could sometimes be diagnostically confused with asthma. More recently, the definition of asthma has been enhanced by the recognition that the airway submucosa of patients with asthma are chronically inflamed with a typical inflammatory infiltrate, and that inflammatory processes are important causes of the chief characteristics of asthma: airway obstruction and BHR. In addition, the loss of reversibility of airway obstruction as a long-term effect of the chronic inflammatory process is recognized:
Bronchial mucosal inflammation and illness severity in response to experimental rhinovirus infection in COPD
Publisher: Elsevier BV
Date: 10-2020
Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper
Publisher: Wiley
Date: 20-01-2019
DOI: 10.1111/ALL.13642
Abstract: Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases.
Association of endopeptidases, involved in SARS‐CoV‐2 infection, with microbial aggravation in sputum of severe asthma
Publisher: Wiley
Date: 25-01-2021
DOI: 10.1111/ALL.14731
Transcription factor interactions in human lung
Publisher: Portland Press Ltd.
Date: 08-1993
DOI: 10.1042/BST021277S
T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED
Publisher: European Respiratory Society (ERS)
Date: 02-2017
DOI: 10.1183/13993003.02135-2016
Abstract: Asthma is characterised by heterogeneous clinical phenotypes. Our objective was to determine molecular phenotypes of asthma by analysing sputum cell transcriptomics from 104 moderate-to-severe asthmatic subjects and 16 nonasthmatic subjects. After filtering on the differentially expressed genes between eosinophil- and noneosinophil-associated sputum inflammation, we used unbiased hierarchical clustering on 508 differentially expressed genes and gene set variation analysis of specific gene sets. We defined three transcriptome-associated clusters (TACs): TAC1 (characterised by immune receptors IL33R , CCR3 and TSLPR ), TAC2 (characterised by interferon-, tumour necrosis factor-α- and inflammasome-associated genes) and TAC3 (characterised by genes of metabolic pathways, ubiquitination and mitochondrial function). TAC1 showed the highest enrichment of gene signatures for interleukin-13/T-helper cell type 2 (Th2) and innate lymphoid cell type 2. TAC1 had the highest sputum eosinophilia and exhaled nitric oxide fraction, and was restricted to severe asthma with oral corticosteroid dependency, frequent exacerbations and severe airflow obstruction. TAC2 showed the highest sputum neutrophilia, serum C-reactive protein levels and prevalence of eczema. TAC3 had normal to moderately high sputum eosinophils and better preserved forced expiratory volume in 1 s. Gene–protein coexpression networks from TAC1 and TAC2 extended this molecular classification. We defined one Th2-high eosinophilic phenotype TAC1, and two non-Th2 phenotypes TAC2 and TAC3, characterised by inflammasome-associated and metabolic/mitochondrial pathways, respectively.
Mitochondrial dysfunction in airways and quadriceps muscle of patients with chronic obstructive pulmonary disease
Publisher: Springer Science and Business Media LLC
Date: 12-10-2020
DOI: 10.1186/S12931-020-01527-5
Abstract: Mitochondrial damage and dysfunction have been reported in airway and quadriceps muscle cells of patients with chronic obstructive pulmonary disease (COPD). We determined the concomitance of mitochondrial dysfunction in these cells in COPD. Bronchial biopsies were obtained from never- and ex-smoker volunteers and COPD patients (GOLD Grade 2) and quadriceps muscle biopsies from the same volunteers in addition to COPD patients at GOLD Grade 3/4 for measurement of mitochondrial function. Decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mtROS) and decreased superoxide dismutase 2 (SOD2) levels were observed in mitochondria isolated from bronchial biopsies from Grade 2 patients compared to healthy never- and ex-smokers. There was a significant correlation between ΔΨm and FEV 1 (% predicted), transfer factor of the lung for carbon monoxide (TLCO C % predicted), 6-min walk test and maximum oxygen consumption. In addition, ΔΨm was also associated with decreased expression levels of electron transport chain (ETC) complex proteins I and II. In quadriceps muscle of Grade 2 COPD patients, a significant increase in total ROS and mtROS was observed without changes in ΔΨm, SOD2 or ETC complex protein expression. However, quadriceps muscle of GOLD Grade 3/4 COPD patients showed an increased mtROS and decreased SOD2 and ETC complex proteins I, II, III and V expression. Mitochondrial dysfunction in the airways, but not in quadriceps muscle, is associated with airflow obstruction and exercise capacity in Grade 2 COPD. Oxidative stress-induced mitochondrial dysfunction in the quadriceps may result from similar disease processes occurring in the lungs.
Health effects of air pollution: what we need to know and to do in the next decade
Publisher: AME Publishing Company
Date: 04-2019
Differential patterns of histone acetylation in inflammatory bowel diseases
Publisher: Springer Science and Business Media LLC
Date: 27-01-2011
Abstract: Post-translational modifications of histones, particularly acetylation, are associated with the regulation of inflammatory gene expression. We used two animal models of inflammation of the bowel and biopsy s les from patients with Crohn's disease (CD) to study the expression of acetylated histones (H) 3 and 4 in inflamed mucosa. Acetylation of histone H4 was significantly elevated in the inflamed mucosa in the trinitrobenzene sulfonic acid model of colitis particularly on lysine residues (K) 8 and 12 in contrast to non-inflamed tissue. In addition, acetylated H4 was localised to inflamed tissue and to Peyer's patches (PP) in dextran sulfate sodium (DSS)-treated rat models. Within the PP, H3 acetylation was detected in the mantle zone whereas H4 acetylation was seen in both the periphery and the germinal centre. Finally, acetylation of H4 was significantly upregulated in inflamed biopsies and PP from patients with CD. Enhanced acetylation of H4K5 and K16 was seen in the PP. These results demonstrate that histone acetylation is associated with inflammation and may provide a novel therapeutic target for mucosal inflammation.
Epigenetics in asthma and COPD
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.BIOCHI.2012.07.017
Abstract: Epigenetic mechanisms are likely to play a role in many complex diseases, the extent of which we only beginning to understand. COPD and asthma are two respiratory diseases subject to strong environmental influences depending on underlying genetic susceptibility. Epigenetic mechanisms such as DNA methylation, histone modification and microRNA may be involved in these processes by modulating environmental effects to influence disease development. Given their demonstrated modifiable nature, epigenetic mechanisms may open new possibilities for therapeutic intervention. Here we give an overview of recent developments in the field of respiratory epigenetics in relation to asthma and COPD in the context of our current understanding of mechanisms leading to such diseases.
Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma
Publisher: BMJ
Date: 07-11-2022
DOI: 10.1136/THORAX-2021-218555
Abstract: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma. We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo. MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity. Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma.
Circulating Leptin Concentrations in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000354191
Abstract: b i Background: /i /b Weight loss is a clinically important risk factor indicating a poor prognosis in chronic obstructive pulmonary disease (COPD). Leptin is an important regulator of food intake and energy expenditure. b i Objectives: /i /b To conduct a meta-analysis to determine whether the level of leptin is related to the disease status of COPD. b i Methods: /i /b Studies published before December 2012 were identified by searching PubMed, Embase and the Cochrane Database. Observational studies comparing circulating leptin levels between COPD patients and healthy controls were included. Data were independently extracted by two investigators and analyzed using Stata 12.0 software. b i Results: /i /b Ten articles were included in the meta-analysis. Circulating leptin levels were correlated with the body mass index (BMI) as well as percent fat mass in stable COPD patients. The correlation coefficient tended to be weaker during exacerbation. A positive correlation between leptin and tumor necrosis factor (TNF)-α levels was found in COPD exacerbations, while it disappeared in patients with stable disease. Most studies indicated that circulating leptin levels in stable COPD patients were not significantly different from those in healthy controls when adjusted for gender and BMI, whilst leptin levels tended to elevate in exacerbation groups. b i Conclusions: /i /b The normal regulatory mechanism of leptin is maintained in stable COPD patients despite weight loss. The additional correlation between leptin and TNF-α during exacerbations may support the closer association of leptin with changes in nutritional parameters and suggests its valuable role in the evaluation of systemic inflammatory responses in COPD patients during exacerbation, which merits further study.
Cellular mechanisms underlying steroid-resistant asthma.
Publisher: European Respiratory Society (ERS)
Date: 30-09-2019
DOI: 10.1183/16000617.0096-2019
Abstract: Severe steroid-resistant asthma is clinically important, as patients with this form of the disease do not respond to mainstay corticosteroid therapies. The heterogeneity of this form of asthma and poor understanding of the pathological mechanisms involved hinder the identification of therapeutic targets and the development of more effective therapies. A major limiting factor in the understanding of severe steroid-resistant asthma is the existence of multiple endotypes represented by different immunological and inflammatory phenotypes, particularly in adults. Several clinical and experimental studies have revealed associations between specific respiratory infections and steroid-resistant asthma in adults. Here, we discuss recent findings from other authors as well as our own studies that have developed novel experimental models for interrogating the association between respiratory infections and severe steroid-resistant asthma. These models have enabled the identification of new therapies using macrolides, as well as several novel disease mechanisms, including the microRNA-21 hosphoinositide 3-kinase/histone deacetylase 2 axis and NLRP3 inflammasomes, and highlight the potential of these mechanisms as therapeutic targets.
Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.JACI.2018.05.026
Abstract: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
Role of inflammatory cells in airway remodeling in COPD
Publisher: Informa UK Limited
Date: 10-2018
DOI: 10.2147/COPD.S176122
Molecular pathogenesis of cigarette smoking–induced stable COPD
Publisher: Wiley
Date: 13-01-2015
DOI: 10.1111/NYAS.12619
Abstract: Inflammation is a central feature of stable chronic obstructive pulmonary disease (COPD) and involves both activation of structural cells of the airways and the lungs and the activation and/or recruitment of infiltrating inflammatory cells. This results in enhanced expression of many pro-inflammatory proteins and reduced expression of some anti-inflammatory mediators. An altered protein expression is generally associated with concomitant changes in gene expression profiles in a cell-specific manner. Increased understanding of the role of transcription factors and of the signaling pathways leading to their activation in stable COPD will provide new targets to enable the development of potential anti-inflammatory drugs. Several new compounds targeting these pathways and/or transcription factors are now in development for the treatment of stable COPD. Furthermore, glucocorticoids drugs already in clinical use act through their own transcription factor, the glucocorticoid receptor, to control the expression of inflammatory and anti-inflammatory genes.
Role of nitric oxide in allergic inflammation and bronchial hyperresponsiveness
Publisher: Elsevier BV
Date: 09-2002
DOI: 10.1016/S0014-2999(02)02237-9
Abstract: The role of nitric oxide (NO) in allergic inflammation and bronchial hyperresponsiveness is unclear. We studied a selective prodrug nitric oxide synthase (NOS)-2 inhibitor, L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (SC-51). In ovalbumin-sensitized and challenged rats, exhaled NO levels increased by 3 h following challenge (3.73 +/- 0.74 ppb P < 0.05), peaking at 9 h (11.0 +/- 2.75 P < 0.01) compared to saline controls (1.87 +/- 0.26 P < 0.05 and 2.81 +/- 0.18 P < 0.01). Immunoreactive lung NOS2 expression was increased in ovalbumin-challenged rats compared with ovalbumin-sensitized, saline-challenged rats at 8 h post-challenge. SC-51 (10 mg/kg p.o.) inhibited allergen-induced increase in exhaled NO levels to 1.3 +/- 0.17 ppb. SC-51 inhibited bronchial hyperresponsiveness in ovalbumin-sensitized and challenged rats (P < 0.05). In sensitized non-exposed rats, SC-51 increased bronchial responsiveness (P < 0.05). SC-51 reduced the allergen-induced increase in bronchoalveolar lavage neutrophils, but caused a nonsignificant reduction in bronchial mucosal eosinophil numbers. NO generated through NOS2 contributes to allergen-induced bronchial hyperresponsiveness but not to bronchial eosinophilia, indicating that these are independently expressed.
p38 Mitogen-Activated Protein Kinase-γ Inhibition by Long-Acting β2Adrenergic Agonists Reversed Steroid Insensitivity in Severe Asthma
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-09-2011
Hydrogen Peroxide in Exhaled Breath Condensate in Patients with Asthma
Publisher: Elsevier BV
Date: 07-2011
Abstract: The measurement of hydrogen peroxide (H(2)O(2)) in exhaled breath condensate (EBC) has been proposed as a noninvasive way of monitoring airway inflammation. However, results from in idual studies on EBC H(2)O(2) evaluation of asthma are conflicting. The purpose of this study was to explore whether EBC H(2)O(2) is elevated in people with asthma and whether it reflects disease severity and disease control or responds to corticosteroid treatment. Studies were identified by searching PubMed, Embase, Cochrane Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and www.controlled-trials.com for relevant reports published before September 2010. Observational studies comparing levels of EBC H(2)O(2) between patients with asthma who were nonsmokers and healthy subjects were included. Data were independently extracted by two investigators and analyzed using Stata 10.0 software. Eight studies (involving 728 participants) were included. EBC H(2)O(2) concentrations were significantly higher in patients with asthma who were nonsmokers compared with healthy subjects, and higher values of EBC H(2)O(2) were observed at each level of asthma, classified either by severity or control level, and the values were negatively correlated with FEV(1). In addition, EBC H(2)O(2) concentrations were lower in patients with asthma treated with corticosteroids than in patients with asthma not treated with corticosteroids. H(2)O(2) might be a promising biomarker for guiding asthma treatment. However, further investigation is needed to establish its role.
Association of Pre-miR-rs2910164 polymorphism with non-small cell lung cancer in an Iranian population
Publisher: European Respiratory Society
Date: 15-09-2018
Epithelial expression and role of secreted STC1 on asthma airway hyperresponsiveness through calcium channel modulation
Publisher: Wiley
Date: 03-06-2021
DOI: 10.1111/ALL.14727
Abstract: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation, and airway remodeling. Airway hyperresponsiveness results from enhanced airway smooth muscle (ASM) contraction potentially under the control of an epithelium‐derived relaxing factor (EpDRF). However, relatively rare is known about EpDRF. We aimed to elucidate the role of epithelium‐derived stanniocalcin‐1 (STC1) on AHR and ASM contraction. Stanniocalcin‐1 levels in the serum of asthmatic patients and healthy volunteers and in bronchoalveolar lavage fluid (BALF) from ovalbumin (OVA)‐challenged mice were measured by ELISA. The effects of exogenous STC1 on AHR and on inflammation were examined in mice. IL‐13 modulation of STC1 mRNA and protein levels was studied in human bronchial epithelial cell lines (16HBE). The function of STC1 on Ca 2+ influx and ASM contraction was examined ex vivo . Serum STC1 was decreased in asthma ( n = 93) compared with healthy volunteers (1071 ± 30.4 vs 1414 ± 75.1 pg/ml, p 0.0001, n = 23) and correlated with asthma control ( p = 0.0270), lung function (FEV1, p = 0.0130), and serum IL‐13 levels ( p = 0.0009). Treatment of ten asthmatic subjects with inhaled corticosteroids/long‐acting beta2‐agonists (ICS/LABA) for 1 year enhanced STC1 expression which correlated with improved asthma control ( p = 0.022). STC1 was mainly expressed in bronchial epithelium and intranasal administration of recombinant human STC1 (rhSTC1) reduced AHR and inflammation in mice. IL‐13 suppressed STC1 release from 16HBE, whereas rhSTC1 blocked store‐operated Ca 2+ entry (SOCE) by suppressing stromal interaction molecule 1 (STIM1) and further inhibited ASM cell contractility by suppressing Ca 2+ ‐dependent myosin light chain (MLC) phosphorylation. Our data indicate that STC1 deficiency in asthmatic airways promotes STIM1 hyperactivity, enhanced ASM contraction, and AHR. STC1 may be a candidate EpDRF.
Molecular mechanisms of corticosteroid actions
Publisher: Elsevier BV
Date: 06-2001
Abstract: Glucocorticoids are the most effective therapeutic agents used for the treatment of chronic inflammatory diseases of the lung. They act by interacting with, and thereby activating, a specific cytoplasmic receptor (GR) which then migrates to the cell nucleus and inhibits inflammatory gene transcription. Inflammatory gene transcription is enhanced by activation of several intracellular signalling pathways which activate transcription factor such as NF-kappaB and AP-1. These transcription factors bind to DNA and induce local unwinding of the DNA structure allowing increased gene transcription. Glucocorticoids interfere with the ability of NF-kappaB and AP-1 to induce transcription by increasing the compaction of unwound chromosomal DNA in a process that involves deacetylation of histone proteins. A small number of asthmatic patients are resistant to the beneficial effects of glucocorticoids. This defect does not appear to be due to a reduced expression of GR but may be associated with a failure of GR to translocate into the nucleus and/or a reduced ability to inhibit AP-1 actions.
B Cells Contribute to the Antitumor Activity of CpG-Oligodeoxynucleotide in a Mouse Model of Metastatic Lung Carcinoma
Publisher: American Thoracic Society
Date: 15-05-2011
Statins as potential therapeutic drug for asthma?
Publisher: Springer Science and Business Media LLC
Date: 24-11-2012
Abstract: Statins are lipid-lowering agents that also exhibit pleiotropic effects in decreasing oxidative stress and inflammation. There have been several published studies reporting the use of statins in the treatment of asthma patients, but their results are not consistent. The aim of this study is to determine whether statins are beneficial for asthma administration, and explore the potential covariables that may affect their clinical effectiveness. A systematic literature search was performed in PubMed, Embase and Cochrane Center Register of Controlled Trials from inception to September 2012. Randomized controlled trials (RCT), retrospective studies and controlled clinical trials which reported the use of statins in the treatment of asthma patients were eligible. Quality evaluation was conducted for RCT using Jadad criteria. A total of 18 articles were included. In our study, we found no conclusive evidence to demonstrate that statins could enhance the lung function in asthmatics, although, they may reduce airway inflammation. Additionally, the results were not consistent across studies with respect to symptoms, quality of life, maintenance medication, asthma hospitalization/emergency department (ED) visits. Statins may reduce airway inflammation in asthmatics, without having a significant effect on lung function. Further large s le and multicenter clinical trials are needed to confirm this and to see if there are more responsive phenotypes of asthma.
How Variability in Clinical Phenotypes Should Guide Research into Disease Mechanisms in Asthma
Publisher: American Thoracic Society
Date: 12-2013
A Preliminary Study of microRNA-208b after Acute Myocardial Infarction: Impact on 6-Month Survival
Publisher: Hindawi Limited
Date: 27-05-2018
DOI: 10.1155/2018/2410451
Abstract: Introduction . miRNAs contribute to a variety of essential biological processes including development, proliferation, differentiation, and apoptosis. Circulating microRNAs are very stable and have shown potential as biomarkers of cardiovascular disease. microRNA-208b expression was increased in the blood of patients with acute myocardial infarction (AMI) and has been proposed as a biomarker for early diagnosis. In this pilot study, we investigate the potential of circulating miR-208b as a prognostic biomarker of 6-month survival in AMI patients. Methods . Plasma s les from 21 patients and 8 age- and gender-matched healthy adults were collected, and circulating levels of miR-208b were detected using quantitative real-time PCR. Results . miR-208b levels were higher in healthy control subjects (9.6-fold P ≤ 0.05 ). Within the AMI patients, the levels of miR-208b were significantly lower in the survivor versus nonsurvivor group (fold change = 6.51 and 14.1, resp. P ≤ 0.05 ). The Kaplan-Meier curve revealed that the 6-month survival time was significantly higher among AMI patients with a relative expression of miR-208b lower than 12.38. The hazard ratio (HR) for the relative expression of miR-208b ( .38 was the reference) was 5.08 (95% CI: 1.13–22.82 P = 0.03 ). Conclusion . Our results showed that elevated miR-208b expression was associated with reduced long-term survival in AMI patients. These pilot data indicate the need for a large follow-up study to confirm whether miR-208b can be used as a predictor of 6-month survival time after AMI.
Synergistic Induction of Endothelin-1 by Tumor Necrosis Factor α and Interferon γ Is due to Enhanced NF-κB Binding and Histone Acetylation at Specific κB Sites
Publisher: Elsevier BV
Date: 09-2009
Rhinovirus Infection Induces Degradation of Antimicrobial Peptides and Secondary Bacterial Infection in Chronic Obstructive Pulmonary Disease
Publisher: American Thoracic Society
Date: 12-2012
Evaluation of Innate Immune Mediators Related to Respiratory Viruses in the Lung of Stable COPD Patients
Publisher: MDPI AG
Date: 10-06-2020
DOI: 10.3390/JCM9061807
Abstract: Background: Little is known about the innate immune response to viral infections in stable Chronic Obstructive Pulmonary Disease (COPD). Objectives: To evaluate the innate immune mediators related to respiratory viruses in the bronchial biopsies and lung parenchyma of stable COPD patients. Methods: We evaluated the immunohistochemical (IHC) expression of Toll-like receptors 3-7-8-9 (TLR-3-7-8-9), TIR domain-containing adaptor inducing IFNβ (TRIF), Interferon regulatory factor 3 (IRF3), Phospho interferon regulatory factor 3 ( pIRF3), Interferon regulatory factor 7 (IRF7), Phospho interferon regulatory factor 7 (pIRF7), retinoic acid-inducible gene I (RIG1), melanoma differentiation-associated protein 5 (MDA5), Probable ATP-dependent RNA helicase DHX58 ( LGP2), Mitochondrial antiviral-signaling protein (MAVS), Stimulator of interferon genes (STING), DNA-dependent activator of IFN regulatory factors (DAI), forkhead box protein A3(FOXA3), Interferon alfa (IFNα), and Interferon beta (IFNβ) in the bronchial mucosa of patients with mild/moderate (n = 16), severe/very severe (n = 18) stable COPD, control smokers (CS) (n = 12), and control non-smokers (CNS) (n = 12). We performed similar IHC analyses in peripheral lung from COPD (n = 12) and CS (n = 12). IFNα and IFNβ were assessed in bronchoalveolar lavage (BAL) supernatant from CNS (n = 8), CS (n = 9) and mild/moderate COPD (n = 12). Viral load, including adenovirus-B, -C, Bocavirus, Respiratory syncytial Virus (RSV),Human Rhinovirus (HRV), Coronavirus, Influenza virus A (FLU-A), Influenza virus B (FLU-B), and Parainfluenzae-1 were measured in bronchial rings and lung parenchyma of COPD patients and the related control group (CS). Results: Among the viral-related innate immune mediators, RIG1, LGP2, MAVS, STING, and DAI resulted well expressed in the bronchial and lung tissues of COPD patients, although not in a significantly different mode from control groups. Compared to CS, COPD patients showed no significant differences of viral load in bronchial rings and lung parenchyma. Conclusions: Some virus-related molecules are well-expressed in the lung tissue and bronchi of stable COPD patients independently of the disease severity, suggesting a “primed” tissue environment capable of sensing the potential viral infections occurring in these patients.
An Integrative Systems Biology Approach to Understanding Pulmonary Diseases
Publisher: Elsevier BV
Date: 06-2010
Abstract: Chronic inflammatory pulmonary diseases such as COPD and asthma are highly prevalent and associated with a major health burden worldwide. Despite a wealth of biologic and clinical information on normal and pathologic airway structure and function, the primary causes and mechanisms of disease remain to a large extent unknown, preventing the development of more efficient diagnosis and treatment. We propose to overcome these limitations through an integrative systems biology research strategy designed to identify the functional and regulatory pathways that play central roles in respiratory pathophysiology, starting with severe asthma. This approach relies on global genome, transcriptome, proteome, and metabolome data sets collected in cross-sectional patient cohorts with high-throughput measurement platforms and integrated with biologic and clinical data to inform predictive multiscale models ranging from the molecular to the organ levels. Working hypotheses formulated on the mechanisms and pathways involved in various disease states are tested through perturbation experiments using model simulation combined with targeted and global technologies in cellular and animal models. The responses observed are compared with those predicted by the initial models, which are refined to account better for the results. Novel perturbation experiments are designed and tested both computationally and experimentally to arbitrate between competing hypotheses. The process is iterated until the derived knowledge allows a better classification and subphenotyping of severe asthma using complex biomarkers, which will facilitate the development of novel diagnostic and therapeutic interventions targeting multiple components of the molecular and cellular pathways involved. This can be tested and validated in prospective clinical trials.
Effect of dexamethasone on interleukin-1beta-(IL-1beta)-induced nuclear factor-kappaB (NF-kappaB) and kappaB-dependent transcription in epithelial cells
Publisher: Wiley
Date: 15-05-1998
DOI: 10.1046/J.1432-1327.1998.2540081.X
Abstract: The production of inflammatory mediators by epithelial cells in inflammatory lung diseases may represent an important target for the anti-inflammatory effects of glucocorticoids. Nuclear factor-kappaB (NF-kappaB) is a major activator of inflammatory genes and has been proposed as a target for inhibition by glucocorticoids. We have used human pulmonary type-II A549 and airway epithelial BEAS-2B cells to investigate the effect of glucocorticoids on NF-kappaB regulation and kappaB-dependent transcription. In A549 cells following interleukin-1beta (IL-1beta) treatment, there was no effect of dexamethasone on the disappearance of I kappaB alpha protein, its subsequent reappearance 90-min later or the rapid induction of I kappaB alpha mRNA and transcription rate. Expression of p65 and p50 105 proteins were also unaffected by dexamethasone. In addition, the rapid IL-1beta-induction of NF-kappaB DNA binding and p65 nuclear localisation was unaffected by short (1-6 hours) dexamethasone pre-treatments. Similarly, BEAS-2B cells showed no effect of dexamethasone on IL-1beta-induced NF-kappaB (p50 65). Stable transfection of a kappaB-dependent reporter in A549 cells resulted in an 8-9-fold activation by IL-1beta or phorbol ester, that was repressed 30-40% by dexamethasone. However, in these cells, IL-1beta induction of inducible nitric oxide synthase, granulocyte-macrophage colony stimulating factor and cyclooxygenase-2 mRNA showed 70-90% repression by dexamethsone. We, therefore, conclude that in these epithelial cells, the repressive effects of glucocorticoids are not mediated by up-regulation of I kappaB alpha, decreased p50 65 gene expression or inhibition of NF-kappaB DNA binding. Furthermore, since the maximal repression of IL-1beta or phorbol-ester-induced kappaB-dependent transcription by dexamethasone was less than 40%, simple inhibition of kappaB-dependent transcription cannot by itself account for the full repressive effects of glucocorticoids observed in these cells.
Adoptive Immunotherapy with Cl-IB-MECA-Treated CD8+ T Cells Reduces Melanoma Growth in Mice
Publisher: Public Library of Science (PLoS)
Date: 24-09-2012
Corticosteroid responsiveness and resistance in severe asthma
Publisher: European Respiratory Society
Date: 06-2019
Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.DRUDIS.2016.10.011
Abstract: Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and non-governmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathways-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this.
Treatable traits in the European U‐BIOPRED adult asthma cohorts
Publisher: Wiley
Date: 12-11-2018
DOI: 10.1111/ALL.13629
New treatments for COPD
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.COPH.2013.03.014
Abstract: Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide. It is characterised by chronic inflammation in the lungs that leads to progressive chronic airflow obstruction. The main strategy for treating COPD is control of the chronic inflammation. However, current anti-inflammatory treatments fail to prevent disease progression. New long-acting bronchodilators and their combinations are currently under development. Research has been focused on identifying the key inflammatory regulators. CXCR2 antagonists inhibit neutrophilic inflammation inhibitors of phosphodiesterase-4 (PDE4), p38 mitogen-activated protein kinase (p38), Janus kinases and IL-6 have also shown some promising effects. There is an emerging need for identification of key modulators of the oxidative stress-regulated corticosteroid function aiming the development of monotherapies which will resolve any side effects issues currently faced.
Transcription factors and asthma
Publisher: European Respiratory Society (ERS)
Date: 07-1998
DOI: 10.1183/09031936.98.12010221
Abstract: Asthma is characterized by the expression of multiple genes for inflammatory proteins, such as cytokines, enzymes, receptors and adhesion molecules. This is orchestrated by transcription factors, which are proteins that bind to the promoter regions of these genes and may be activated by inflammatory stimuli, such as cytokines. Several transcription factors are involved in asthmatic inflammation, including nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), nuclear factor of activated T-cells (NF-AT), cyclic AMP response element binding protein (CREB) and signal transduction-activated transcription factors (STAT). These transcription factors lead to coordinated expression of multiple inflammatory genes. There is increasing evidence that synergistic interaction of these transcription factors (e.g. NF-kappaB and AP-1) results in the optimal expression of particular genes, resulting in the specific inflammatory pattern seen in asthmatic airways. Transcription factors are a target for antiasthma therapy. Corticosteroids activate glucocorticoid receptors, which themselves are transcription factors, and interact with other transcription factors to inhibit their actions. The interaction between transcription factors may be important in lifying and inhibiting the inflammatory process. Many transcription factors interact with a large co-activator molecule CREB-binding protein (CBP) that coordinates the activation of several transcription factors and controls transcription through the regulation of deoxyribonucleic acid coiling around histone residues in the chromatin structure. Understanding transcription factors in asthma has given new insights into the complex chronic inflammatory process, the mechanism of action of corticosteroids, and may lead to new approaches to therapy in the future.
Corticosteroids
Publisher: Springer International Publishing
Date: 2019
FIZZ2 as a Biomarker for Acute Exacerbation of Chronic Obstructive Pulmonary Disease
Publisher: Springer Science and Business Media LLC
Date: 22-10-2021
DOI: 10.1007/S00408-021-00483-1
Abstract: Found in inflammatory zone 2 (FIZZ2) is associated with lung inflammation. The aim of the study was to investigate the expression and utility of FIZZ2 as a marker for chronic obstructive pulmonary disease (COPD). Immunohistochemistry was used to detect the expression of FIZZ2 in COPD. The serum concentration of FIZZ2 was measured by enzyme-linked immunosorbent assay and the episodes of acute exacerbations of COPD (AECOPD) in the following year were recorded. FIZZ2 expression was elevated in bronchial epithelial cells (0.217 ± 0.021 vs 0.099 ± 0.010, p < 0.0001) and negatively correlated with the pulmonary function (FEV1/FVC%) (p = 0.0149) and positively correlated with the smoking index (p = 0.0241). Serum level of FIZZ2 in COPD were significantly higher than that in healthy controls (561.6 ± 70.71 vs 52.24 ± 20.52 pg/ml, p < 0.0001) and increased with the COPD severity. Serum levels of FIZZ2 negatively correlated with the pulmonary function [Forced Vital Capacity (FVC), Forced Expiratory Volume (FEV1), FEV1%, FEV1/FVC) (r = - 0.3086, - 0.3529, - 0.3343, and - 0.2676, respectively, p = 0.0003, p < 0.0001, p < 0.0001, p = 0.0014). The expression of human serum FIZZ2 was positively correlated with the smoking index (r = 0.2749, p = 0.0015). There was a positive correlation between the FIZZ2 concentration and the frequency of AECOPD episodes in the following year (r = 0.7291, p < 0.0001). FIZZ2 expression was elevated in patients with COPD and its serum concentration might be a potential biomarker for AECOPD.
Corticosteroids: limitations and future prospects for treatment of severe inflammatory disease
Publisher: Elsevier BV
Date: 12-2004
Transcription factors
Publisher: Wiley
Date: 11-1995
DOI: 10.1111/J.1365-2222.1995.TB00421.X
Abstract: Follow-up care is crucial but challenging for disease management particularly in rural areas with limited healthcare resources and clinical capacity, yet few studies have been conducted from the perspective of rural primary care physicians (PCPs). We assessed the frequency of follow-up care delivered by rural PCPs for hypertension and type 2 diabetes - the two most common long-term conditions. We conducted a multi-centre, self-administered survey study built upon existing general practice course programmes for rural PCPs in four provinces. Information on follow-up care delivery were collected from rural PCPs attending centralised in-class teaching sessions using a set of close-ended, multiple choice questions. Binary logistic regression analysis was performed to examine physician-level factors associated with non-attainment of the target frequency of follow-up care for hypertension and type 2 diabetes, respectively. The final s le consisted of rural PCPs from 52 township-level regions. The Complex S les module was used in the statistical analysis to account for the multistage s le design. The overall response rate was 91.4%. Around one fifth of PCPs in rural practices did not achieve the target frequency of follow-up care delivery (18.7% for hypertension 21.6% for type 2 diabetes). Higher education level of physicians, increased volume of daily patients seen, and no provision of home visits were risk factors for non-attainment of the target frequency of follow-up care for both conditions. Moreover, village physicians with less working experiences tended to have less frequent follow-up care delivery in type 2 diabetes management. Efforts that are solely devoted to enhancing rural physicians' education may not directly translate into strong motivation and active commitment to service provision given the possible existence of clinical inertia and workload-related factors. Risk factors identified for target non-attainment in the follow-up care delivery may provide areas for capacity building programmes in rural primary care practice.
Is Fezakinumab, an anti-IL22 antibody, a putative novel therapy for a subset of severe asthma?
Publisher: European Respiratory Society
Date: 28-09-2019
H influenzae & M catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation
Publisher: Authorea, Inc.
Date: 29-12-2022
DOI: 10.22541/AU.167228469.92826361/V1
Abstract: Background. Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. Methods. Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data was analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs). Results. α- ersity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis, and Haemophilus influenzae and Tropheryma whipplei, respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α- ersity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei, and Haemophilus influenzae and Moraxella catarrhalis , respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella , Neisseria and Veillonella species and Haemophilus parainfluenzae . Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack-years of smoking. α- and β- ersities were stable at one year. Conclusions. Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL-13 Type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.
Mitochondrial ROS and NLRP3 inflammasome in acute ozone-induced murine model of airway inflammation and bronchial hyperresponsiveness
Publisher: Informa UK Limited
Date: 27-06-2019
DOI: 10.1080/10715762.2019.1630735
Abstract: Oxidative stress is a key mechanism underlying ozone-induced lung injury. Mitochondria can release mitochondrial reactive oxidative species (mtROS), which may lead to the activation of NLRP3 inflammasome. The goal of this study was to examine the roles of mtROS and NLRP3 inflammasome in acute ozone-induced airway inflammation and bronchial hyperresponsiveness (BHR). C57/BL6 mice (
Multidimensional endotyping using nasal proteomics predicts molecular phenotypes in the asthmatic airways
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.JACI.2022.06.028
Abstract: Unsupervised clustering of biomarkers derived from noninvasive s les such as nasal fluid is less evaluated as a tool for describing asthma endotypes. We sought to evaluate whether protein expression in nasal fluid would identify distinct clusters of patients with asthma with specific lower airway molecular phenotypes. Unsupervised clustering of 168 nasal inflammatory and immune proteins and Shapley values was used to stratify 43 patients with severe asthma (endotype of noneosinophilic asthma) using a 2 "modeling blocks" machine learning approach. This algorithm was also applied to nasal brushings transcriptomics from U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes). Feature reduction and functional gene analysis were used to compare proteomic and transcriptomic clusters. Gene set variation analysis provided enrichment scores of the endotype of noneosinophilic asthma protein signature within U-BIOPRED sputum and blood. The nasal protein machine learning model identified 2 severe asthma endotypes, which were replicated in U-BIOPRED nasal transcriptomics. Cluster 1 patients had significant airway obstruction, small airways disease, air trapping, decreased diffusing capacity, and increased oxidative stress, although only 4 of 18 were current smokers. Shapley identified 20 cluster-defining proteins. Forty-one proteins were significantly higher in cluster 1. Pathways associated with proteomic and transcriptomic clusters were linked to T Protein or gene analysis may indicate molecular phenotypes within the asthmatic lower airway and provide a simple, noninvasive test for non-type 2 immune response asthma that is currently unavailable.
Inducible nitric oxide synthase after sensitization and allergen challenge of Brown Norway rat lung
Publisher: Wiley
Date: 07-1997
Bromodomain and extra‐terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension
Publisher: Wiley
Date: 18-08-2016
DOI: 10.1111/RESP.12872
Oestrogen receptors and effects of oestradiol administration on mRNA synthesis in the limbic system of the neonatal female rat
Publisher: Bioscientifica
Date: 1989
Abstract: There is sexual dimorphism of specific species of mRNA in the neonatal rat brain and this sexual dimorphism may be imprinted by steroids of testicular origin during the perinatal period. According to current theories, only aromatizable androgens may cause sexual differentiation of sexual behaviour and function in the adult. The effects of oestradiol benzoate on mRNA synthesis in the neonatal female limbic system were therefore studied. In addition, cytosolic and nuclear oestrogen receptors were measured after administration of testosterone propionate, oestradiol benzoate or dihydrotestosterone (DHT). An attempt was made to distinguish between the brain oestrogen receptor and the plasma oestrogen-binding protein, alphafoetoprotein (AFP) by isoelectric focussing. After injection of 50 μg oestradiol benzoate s.c. to neonatal female rats, the expression of mRNA coding for sexually dimorphic proteins appeared to be changed to a male-type pattern. The overall density of labelling was noticeably greater and specific changes in labelled proteins were observed. These effects were observed within 3 h of injection. Both testosterone and oestradiol caused a marked depletion of cytosolic oestrogen receptors in the limbic system whereas DHT was ineffective in this respect. Nuclear receptors were present in equal abundance in male- and female-derived nuclei and only oestradiol was able to cause a significant ( P 0·025) increase in nuclear oestrogen receptors. The receptor and AFP could be distinguished by isoelectric focussing, since the pI of the receptor was 7·05, while that of AFP was 4·5. These results are consistent with the possibility that oestradiol alters transcription in the neonatal rat brain and may do this through the oestrogen receptor. Nevertheless, it is also possible that oestradiol could alter post-transcriptional events such as the stability of mRNA or the binding of tRNA to the polysomal complex. Journal of Endocrinology (1989) 120, 83–88
Characteristics of asthma in U-BIOPRED severe and non-severe cohorts with distinct biomarker profiles
Publisher: European Respiratory Society
Date: 09-2015
Systematic assessment of difficult-to-treat asthma
Publisher: European Respiratory Society (ERS)
Date: 09-2003
DOI: 10.1183/09031936.03.00017003
Abstract: Five per cent of asthmatics remain symptomatic despite high-dose treatment. The aim of the study was to investigate how often such difficult-to-treat asthma is due to intractable asthma, misdiagnosis, non-adherence with therapy, or psychiatric problems. Difficult asthma was defined as persistence of symptoms despite treatment at step 4 of British guidelines or requirement for long-term oral glucocorticoids (step 5). One-hundred patients with a respiratory physician diagnosis of asthma were investigated in a single tertiary respiratory unit in an open and descriptive study. Twelve of the patients studied did not have asthma and a further seven had additional diagnoses. Of the remainder, 55 had an asthma diagnosis confirmed by demonstration of reversible airflow narrowing or peak flow variability, whilst 20 did not. Non-compliance with prednisolone therapy was more frequent in the 55 with confirmed asthma (nine of 18 prescribed oral prednisolone at a dose of > or = 15 mg x day(-1)) and was not detected in the "unconfirmed asthma" group. There were no other significant differences between these groups. A major psychiatric component was detected in 10 patients. Systematic evaluation of difficult asthma is useful as it can identify alternative or additional diagnoses, psychiatric illness or nonconcordance with therapy in a substantial proportion of cases (32% in the present series).
Cigarette smoke induces CXCL8 production by human neutrophils via activation of TLR9 receptor
Publisher: European Respiratory Society (ERS)
Date: 19-10-2009
DOI: 10.1183/09031936.00062209
Abstract: Chronic obstructive pulmonary disease (COPD) is a major health problem and cigarette smoke is the main risk factor for the development of COPD. The characteristic changes in airway morphology, inflammatory cell infiltration and mediator expression in COPD may result from direct effects of cigarette smoke on airway cells. Toll-like receptors (TLRs) are key elements in pathogen recognition by the host immune system. Although TLRs have been intensely studied in innate immunity and infection, their critical role in noninfectious challenges has only recently emerged. Here we investigate whether cigarette smoke induces TLR9 signalling in human neutrophils. Human neutrophils were isolated from buffy coat and exposed to cigarette smoke extract. The production of CXC chemokine ligand (CXCL)8 was measured as a functional readout and the role of TLR9 signalling was investigated. Cigarette smoke extract induced CXCL8 release via TLR9 activation in neutrophils, which was confirmed in TLR9 stably transfected human embryonic kidney 293 cells. Moreover, cigarette smoke extract upregulated the expression of TLR9 and the upregulated expression was suppressed by N-acetylcysteine. TLR9 mediates cigarette smoke-induced release of CXCL8 and this may contribute to the accumulation of neutrophils and inflammation within the airways of smokers.
Divergent effect of mometasone on human eosinophil and neutrophil apoptosis
Publisher: Elsevier BV
Date: 08-2002
DOI: 10.1016/S0024-3205(02)01921-5
Abstract: Mometasone is a potent synthetic glucocorticoid, which is under development as an inhaled preparation for the treatment of asthma. Previous studies have suggested that glucocorticoids have direct effects on human eosinophil and neutrophil apoptosis. The present study was designed to characterize the effects of mometasone on constitutive apoptosis and cytokine-afforded survival in isolated human eosinophils and neutrophils. The isolated eosinophils or neutrophils were cultured in vitro, and apoptosis was assessed by flow cytometric analysis of relative DNA content, by annexin-V binding and morphological analysis. Mometasone enhanced constitutive human eosinophil apoptosis in a concentration-dependent manner. The maximal enhancement of eosinophil apoptosis was 2.1-fold with an EC(50) value of 5.63 +/- 2.33 nM. This enhancing effect was reversed by the glucocorticoid receptor antagonist, mifepristone. In the presence of added cytokines, mometasone reversed tumor necrosis factor -alpha-induced eosinophil survival but not that afforded by interleukin -5. In contrast, mometasone inhibited human neutrophil apoptosis in a concentration-dependent manner. The maximal inhibition of neutrophil apoptosis was 50% with an EC(50) value of 0.17 +/- 0.03 nM. The inhibitory effect was partly reversed by mifepristone. In the presence of added cytokines, mometasone further enhanced neutrophil survival induced by the granulocyte-macrophage colony-stimulating factor and leukotriene B(4). The present data suggests that mometasone has opposite effects on apoptosis of human eosinophils and neutrophils at clinically relevant drug concentrations via an effect on glucocorticoid receptor.
Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis
Publisher: Springer Science and Business Media LLC
Date: 14-10-2014
Ezrin, a Membrane Cytoskeleton Cross-Linker Protein, as a Marker of Epithelial Damage in Asthma
Publisher: American Thoracic Society
Date: 15-02-2019
The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts
Publisher: Elsevier BV
Date: 07-2023
Radiomics for severe asthma phenotyping and endotyping
Publisher: European Respiratory Society
Date: 04-09-2022
How Do Corticosteroids Work in Asthma?
Publisher: American College of Physicians
Date: 02-09-2003
Albuterol-induced downregulation of Gsα accounts for pulmonary β2-adrenoceptor desensitization in vivo
Publisher: American Society for Clinical Investigation
Date: 07-2000
DOI: 10.1172/JCI8374
A genome-wide association study implicates the pleiotropic effect of NMUR2 on asthma and COPD
Publisher: Springer Science and Business Media LLC
Date: 21-12-2022
DOI: 10.1038/S41598-022-24766-6
Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are two distinct diseases that are associated with chronic inflammation. They share common features in terms of their advanced stages and genetic factors. This study aimed to identify novel genes underlying both asthma and COPD using genome-wide association study (GWAS) to differentiate between the two diseases. We performed a GWAS of asthma and COPD in 7828 Koreans from three hospitals. In addition, we investigated genetic correlations. The UK Biobank dataset was used for the replication studies. We found that rs2961757, located near neuromedin U receptor 2 ( NMUR2 ) on chromosome 5, was genome-wide significant ( $${\\upbeta }_{\\mathrm{Asthma}-\\mathrm{COPD}}$$ β Asthma - COPD = 0.44, P -value Asthma-COPD = 3.41 × 10 −8 ), and significant results were replicated with the UK Biobank data ( $${\\upbeta }_{\\mathrm{Asthma}-\\mathrm{COPD}}$$ β Asthma - COPD = 0.04, P -value Asthma-COPD = 0.0431). A positive genetic correlation was observed between asthma and COPD (39.8% in the Korean dataset and 49.8% in the UK Biobank dataset). In this study, 40–45% of the genetic effects were common to asthma and COPD. Moreover, NMUR2 increases the risk of asthma development and suppresses COPD development. This indicates that NMUR2 allows for better differentiation of both diseases, which can facilitate tailored medical therapy.
Adverse roles of mast cell chymase-1 in COPD
Publisher: European Respiratory Society (ERS)
Date: 07-2022
DOI: 10.1183/13993003.01431-2021
Abstract: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed. Human chymase (hCMA)1 and its orthologue mCMA1/mouse mast cell protease (mMCP)5 are exocytosed from activated mast cells and have adverse roles in numerous disorders, but their role in COPD is unknown. We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5 -deficient ( −/− ) mice to evaluate this protease's role and potential for therapeutic targeting in CS-induced experimental COPD. In addition, we used ex vivo/in vitro studies to define mechanisms. The levels of hCMA1 mRNA and CMA1 + mast cells were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated mast cell numbers and mMCP5 protein were increased in lung tissues of wild-type mice with experimental COPD. mmcp5 −/− mice were protected against CS-induced inflammation and macrophage accumulation, airway remodelling, emphysema and impaired lung function in experimental COPD. CS extract challenge of co-cultures of mast cells from wild-type, but not mmcp5 −/− mice with wild-type lung macrophages increased in tumour necrosis factor (TNF)-α release. It also caused the release of CMA1 from human mast cells, and recombinant hCMA-1 induced TNF-α release from human macrophages. Treatment with CMA1 inhibitor potently suppressed these hallmark features of experimental COPD. CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD.
Targeting Th2 Cells in Asthmatic Airways
Publisher: Springer Japan
Date: 2010
Breaking news: DNA damage and repair pathways in COPD and implications for pathogenesis and treatment
Publisher: European Respiratory Society (ERS)
Date: 10-2018
New targets for drug development in asthma
Publisher: Elsevier BV
Date: 09-2008
High concentrations of B-adrenergic agonists inhibit DNA binding of glucocorticoids in human lung in vitro
Publisher: Portland Press Ltd.
Date: 05-1995
DOI: 10.1042/BST023217S
Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor κB and c-Jun N-terminal kinase activation
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JACI.2013.05.028
Abstract: Although inhaled glucocorticoids are the mainstays of asthma treatment, they are poorly effective at treating and preventing virus-induced asthma exacerbations. The major viruses precipitating asthma exacerbations are rhinoviruses. We sought to evaluate whether rhinovirus infection interferes with the mechanisms of action of glucocorticoids. Cultured primary human bronchial or transformed (A549) respiratory epithelial cells were infected with rhinovirus 16 (RV-16) before dexamethasone exposure. Glucocorticoid receptor (GR) α nuclear translocation, glucocorticoid response element (GRE) binding, and transactivation/transrepression functional readouts were evaluated by using immunocytochemistry, Western blotting, DNA binding assays, real-time quantitative PCR, coimmunoprecipitation, and ELISA techniques. Specific inhibitors of c-Jun N-terminal kinase (JNK) and of IκB kinase (IKK) were used to investigate the involvement of intracellular signaling pathways. RV-16 infection impaired dexamethasone-dependent (1) inhibition of IL-1β-induced CXCL8 release, (2) induction of mitogen-activated protein kinase phosphatase 1 gene expression, and (3) binding of GR to GREs in airway epithelial cells. This was associated with impaired GRα nuclear translocation, as assessed by means of both immunochemistry (54.0% ± 6.8% vs 24.7% ± 3.8% GR-positive nuclei after 10 nmol/L dexamethasone treatment in sham- or RV-16-infected cells, respectively P < .01) and Western blotting. RV-16 infection induced nuclear factor κB activation and GRα phosphorylation, which were prevented by inhibitors of IKK2 and JNK, respectively. In rhinovirus-infected cells the combination of JNK and IKK2 inhibitors totally restored dexamethasone suppression of CXCL8 release, induction of mitogen-activated protein kinase phosphatase 1 gene expression, and GRα nuclear translocation. RV-16 infection of human airway epithelium induces glucocorticoid resistance. Inhibition of RV-16-induced JNK and nuclear factor κB activation fully reversed rhinovirus impairment of both GRα nuclear translocation and the transactivation/transrepression activities of glucocorticoids.
Late Breaking Abstract - Microbiome-driven clusters in severe asthma derived from induced sputum: identification and stability over time
Publisher: European Respiratory Society
Date: 28-09-2019
Late Breaking Abstract - Matrix metalloproteinases in serum and sputum reflect distinct processes of relevance to asthma
Publisher: European Respiratory Society
Date: 28-09-2019
BET Bromodomains Regulate Transforming Growth Factor-β-induced Proliferation and Cytokine Release in Asthmatic Airway Smooth Muscle
Publisher: Elsevier BV
Date: 04-2015
Steroid resistance in asthma: a major problem requiring novel solutions or a non-issue?
Publisher: Elsevier BV
Date: 06-2004
Differential IκB Kinase Activation and IκBα Degradation by Interleukin-1β and Tumor Necrosis Factor-α in Human U937 Monocytic Cells
Publisher: Elsevier BV
Date: 07-1999
Cigarette Smoke Exposure Alters mSin3a and Mi-2α/β Expression; implications in the control of pro-inflammatory gene transcription and glucocorticoid function
Publisher: Springer Science and Business Media LLC
Date: 16-07-2010
Abstract: The key co-repressor complex components HDAC-2, Mi-2α/β and mSin3a are all critical to the regulation of gene transcription. HDAC-2 function is impaired by oxidative stress in a PI3Kδ dependant manner which may be involved in the chronic glucocorticoid insensitive inflammation in the lungs of COPD patients. However, the impact of cigarette smoke exposure on the expression of mSin3a and Mi2α/β and their role in glucocorticoid responsiveness is unknown. Wild type, PI3Kγ knock-out (PI3Kγ -/- ) and PI3K kinase dead knock-in (PI3Kδ D910/A910 ) transgenic mice were exposed to cigarette smoke for 3 days and the expression levels of the co-repressor complex components HDAC-2, mSin3a, Mi-2α and Mi-2β and HDAC-2 activity in the lungs were assessed. Cigarette smoke exposure impaired glucocorticoid function and reduced HDAC-2 activity which was protected in the PI3Kδ D910/A910 mice. Both mSin3a and Mi-2α protein expression was reduced in smoke-exposed mice. Budesonide alone protected mSin3a protein expression with no additional effect seen with abrogation of PI3Kγ/δ activity, however Mi-2α, but not Mi-2β, expression was protected in both PI3Kδ D910/A910 and PI3Kγ -/- budesonide-treated smoke-exposed mice. The restoration of glucocorticoid function coincided with the protection of both HDAC activity and mSin3a and Mi-2α protein expression. Cigarette smoke exposure induced glucocorticoid insensitivity and alters co-repressor activity and expression which is prevented by blockade of PI3K signaling with glucocorticoid treatment. Inhibition of PI3Kδ signalling in combination with glucocorticoid treatment may therefore provide a therapeutic strategy for restoring oxidant-induced glucocortiocid unresponsiveness.
Plasmacytoid Dendritic Cells Alter the Antitumor Activity of CpG-Oligodeoxynucleotides in a Mouse Model of Lung Carcinoma
Publisher: The American Association of Immunologists
Date: 15-10-2010
Abstract: The effect of CpG-oligodeoxynucleotides (CpG) has been studied on a number of tumors. Although CpG may facilitate tumor regression in mouse models of melanoma, its activity in lung cancer is unclear. The aim of our study was to elucidate the effect of CpG (0.5–50 μg/mouse) in a mouse model of Lewis lung carcinoma cell-induced lung cancer. Lung tumor growth increased at 3 and 7 d after a single administration of CpG. This was associated with a greater influx of plasmacytoid dendritic cells (pDCs), immature myeloid dendritic cells, and greater recruitment of regulatory T cells. Depletion of pDCs using a specific Ab (m927) reversed the immune-suppressive environment and resulted in a decreased lung tumor burden, accompanied by a greater influx of active myeloid dendritic cells and CD8+ T cells, and a higher production of Th1- and Th17-like cytokines. Furthermore, the rate of apoptosis in the lungs of mice treated with CpG increased following the depletion of pDCs. CpG treatment alone does not lead to tumor regression in the lung. However, ablation of pDCs renders CpG a good adjuvant for lung cancer chemotherapy in this experimental model.
Sputum myeloperoxidase in chronic obstructive pulmonary disease
Publisher: Springer Science and Business Media LLC
Date: 03-03-2014
Abstract: Airway inflammation, especially neutrophilic airway inflammation, is a cardinal pathophysiologic feature in chronic obstructive pulmonary disease (COPD) patients. The ideal biomarkers characterizing the inflammation might have important potential clinical applications in disease assessment and therapeutic intervention. Sputum myeloperoxidase (MPO) is recognized as a marker of neutrophil activity. The purpose of this meta-analysis is to determine whether sputum MPO levels could reflect disease status or be regulated by regular medications for COPD. Studies were identified by searching PubMed, Embase, the Cochrane Database, CINAHL and www.controlled-trials.com for relevant reports published before September 2012. Observational studies comparing sputum MPO in COPD patients and healthy subjects or asthmatics, or within the COPD group, and studies comparing sputum MPO before and after treatment were all included. Data were independently extracted by two investigators and analyzed using STATA 10.0 software. A total of 24 studies were included in the meta-analysis. Sputum MPO levels were increased in stable COPD patients when compared with normal controls, and this increase was especially pronounced during exacerbations as compared with MPO levels during the stable state. Theophylline treatment was able to reduce MPO levels in COPD patients, while glucocorticoid treatment failed to achieve the same result. Sputum MPO might be a promising biomarker for guiding COPD management however, further investigations are needed to confirm this.
PHF11 and DPP10: A Tale of Two Genes in Asthma
Publisher: S. Karger AG
Date: 2010
DOI: 10.1159/000235972
Susceptibility to mycobacterial disease due to mutations in IL-12Rβ1 in three Iranian patients
Publisher: Springer Science and Business Media LLC
Date: 18-12-2017
An adult autosomal recessive chronic granulomatous disease patient with pulmonary Aspergillus terreus infection
Publisher: Springer Science and Business Media LLC
Date: 08-11-2018
Exosomes and Exosomal miRNA in Respiratory Diseases
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/5628404
Abstract: Exosomes are nanosized vesicles released from every cell in the body including those in the respiratory tract and lungs. They are found in most body fluids and contain a number of different biomolecules including proteins, lipids, and both mRNA and noncoding RNAs. Since they can release their contents, particularly miRNAs, to both neighboring and distal cells, they are considered important in cell-cell communication. Recent evidence has shown their possible importance in the pathogenesis of several pulmonary diseases. The differential expression of exosomes and of exosomal miRNAs in disease has driven their promise as biomarkers of disease enabling noninvasive clinical diagnosis in addition to their use as therapeutic tools. In this review, we summarize recent advances in this area as applicable to pulmonary diseases.
Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats
Publisher: European Respiratory Society (ERS)
Date: 06-08-2010
DOI: 10.1183/09031936.00028310
Abstract: Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points. Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg·kg⁻¹·day⁻¹, 1.25 mg·kg⁻¹ and 2.5 mg·kg⁻¹·48 h⁻¹) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression. Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro. Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.
Neutrophilic Asthma
Publisher: Elsevier BV
Date: 04-2018
p65-activated Histone Acetyltransferase Activity Is Repressed by Glucocorticoids
Publisher: Elsevier BV
Date: 08-2001
Glucocorticoids: Effects on Gene Transcription
Publisher: American Thoracic Society
Date: 11-2004
Chymase-1: a MAST-er switch in COPD?
Publisher: European Respiratory Society (ERS)
Date: 12-2022
International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Kian Fan Chung, Sally E. Wenzel, Jan L. Brozek, Andrew Bush, Mario Castro, Peter J. Sterk, Ian M. Adcock, E
Publisher: European Respiratory Society (ERS)
Date: 31-03-2014
The analysis of exosomal micro-RNAs in peripheral blood mononuclear cell-derived macrophages after infection with bacillus Calmette–Guérin by RNA sequencing
Publisher: Medknow
Date: 12-2016
DOI: 10.1016/J.IJMYCO.2016.09.045
Abstract: Tuberculosis (TB) is a major global threat to human health, especially in low-income countries. The diagnosis of TB is challenging because of the limitations of specificity and sensitivity with the current diagnostics. Novel, selective biomarkers for TB would be of great practical value. Exosomes are bioactive vesicles with 30-100nm in diameter, which are secreted from almost all cell types and are found in virtually every human body fluid. Exosomes transport micro-RNAs (miRNAs), which are post-transcriptional regulators of gene expression, around the body and allow miRNAs to modulate biological pathways in target cells. Our aim was to investigate the potential of exosomal miRNAs as biomarkers by examining their release from human monocyte-derived macrophages (MDMs) after infection with Mycobacterium using miRNA sequencing. Human monocytes were obtained from blood and driven to an MDM phenotype using standard protocols. MDMs were infected with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) or left uninfected as control. Exosomes were collected 72 h postinfection from the cell culture medium and subjected to RNA isolation. Small RNA libraries were constructed and RNA sequencing performed. The raw reads were filtered to eliminate adaptor and primer sequences, and the sequences in FASTQ format were run against the mature human miRNA sequences available in miRBase using BLAST software using a Linux operating system. Micro-RNAs were identified using E=0.01 or 1. Infection of MDMs with BCG lead to the release of a number of exosomal miRNAs. These mainly consisted with Let-7 family members, miR-155, miR-146a, miR-145, and miR-21 all of which were predicted to target important immune-related genes and pathways. This study provides evidence for the release of specific miRNAs from BCG-infected MDMs. These results need to be confirmed and the presence of this panel of miRNAs tested in the blood of patients to determine their selectivity and specificity as a diagnostic in patients with TB.
Characterising SARS-CoV-2 transmission via aerosols and effective sampling methods for surveillance
Publisher: European Respiratory Society
Date: 04-09-2022
WITHDRAWN: Prospective direct comparison of biological treatments on severe eosinophilic asthma: Findings from the PRISM study
Publisher: Elsevier BV
Date: 06-2023
Basic science: Epigenetic programming and the respiratory system
Publisher: European Respiratory Society (ERS)
Date: 06-2013
The first U-BIOPRED sputum handprint of severe asthma
Publisher: European Respiratory Society
Date: 09-2015
Decreased Histone Deacetylase Activity in Chronic Obstructive Pulmonary Disease
Publisher: Massachusetts Medical Society
Date: 12-05-2005
DOI: 10.1056/NEJMOA041892
Nitric Oxide in the Pathogenesis and Treatment of Tuberculosis
Publisher: Frontiers Media SA
Date: 12-10-2017
Education is the passport to the future: enabling today's medical teachers to prepare tomorrow's respiratory health practitioners
Publisher: European Respiratory Society (ERS)
Date: 31-08-2014
Identification of the protein kinase C isoenzymes in human lung and airways smooth muscle at the protein and mRNA level
Publisher: Elsevier BV
Date: 07-1997
DOI: 10.1016/S0006-2952(97)00165-2
Abstract: The protein kinase C (PKC) isoenzymes expressed by human peripheral lung and tracheal smooth muscle resected from in iduals undergoing heart-lung transplantation were identified at the protein and mRNA level. Western immunoblot analyses of human lung identified multiple PKC isoenzymes that were differentially distributed between the soluble and particulate fraction. Thus, PKC alpha, PKC betaII, PKC epsilon, and PKC zeta were recovered predominantly in the soluble fraction whereas the eta isoform was membrane-associated together with trace amounts of PKC alpha and PKC epsilon. PKC beta1-like immunoreactivity was occasionally seen although the intensity of the band was uniformly weak. Immunoreactive bands corresponding to PKCs gamma, delta, or theta were never detected. Reverse transcription-polymerase chain reaction (RT-PCR) of RNA extracted from human lung using oligonucleotide primer pairs that recognise unique sequences in each of the PKC genes lified cDNA fragments that corresponded to the predicted sizes of PKC alpha, PKC betaI, PKC betaII, PKC epsilon, PKC zeta, and PKC eta (consistent with the expression of PKC isoenzyme protein) and, in addition, mRNA for PKC delta PCR fragments of the expected size for the supposedly muscle-specific isoform, PKC theta, or the atypical isoenzyme, PKC lambda, were never obtained. The complement and distribution of PKC isoforms in human trachealis were similar, but not identical, to human lung. Thus, immunoreactive bands corresponding to the alpha, betaI, betaII, epsilon, and zeta isoenzymes of PKC were routinely labelled in the cytosolic fraction. In the particulate material PKC alpha, PKC epsilon, PKC alpha, PKC eta, and PKC mu were detected by immunoblotting. With the exception of PKC zeta, RT-PCR analyses confirmed the expression of the PKC isoforms detected at the protein level and, in addition, identified mRNA for PKC delta. Collectively, these data clearly demonstrate the expression of multiple PKC isoenzymes in human lung and tracheal smooth muscle, suggesting that they subserve erse multifunctional roles in these tissues.
Integrated analysis reveals lung fibrinogen gamma chain as a biomarker for chronic obstructive pulmonary disease
Publisher: AME Publishing Company
Date: 12-2021
DOI: 10.21037/ATM-21-5974
MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase–mediated suppression of histone deacetylase 2
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JACI.2016.04.038
Abstract: Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is h ered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease. We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches. Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated. Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21-specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens. We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma.
Vitamin D Metabolism Is Dysregulated in Asthma and Chronic Obstructive Pulmonary Disease
Publisher: American Thoracic Society
Date: 08-2020
“International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.” Kian Fan Chung, Sally E. Wenzel, Jan L. Brozek, et al. Eur Respir J 2014; 43: 343–373.
Publisher: European Respiratory Society (ERS)
Date: 06-2022
Induction of Phosphodiesterases 3B, 4A4, 4D1, 4D2, and 4D3 in Jurkat T-cells and in Human Peripheral Blood T-lymphocytes by 8-Bromo-cAMP and Gs-coupled Receptor Agonists
Publisher: Elsevier BV
Date: 08-1998
Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD
Publisher: American Physiological Society
Date: 15-11-2015
DOI: 10.1152/AJPLUNG.00077.2015
Abstract: In chronic obstructive pulmonary disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. Glycogen synthase-3β (GSK3β) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of phospho-GSK3β-Ser9, a marker of GSK3β inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers, and nonsmokers. We observed increased levels of phospho-GSK3β-Ser9 in monocytes, alveolar macrophages, and bronchial epithelial cells from COPD patients and control smokers compared with nonsmokers. Pharmacological inactivation of GSK3β did not affect CXCL8 or granulocyte-macrophage colony-stimulating factor (GM-CSF) expression but resulted in glucocorticoid insensitivity in vitro in both inflammatory and structural cells. Further mechanistic studies in monocyte and bronchial epithelial cell lines showed that GSK3β inactivation is a common effector of oxidative stress-induced activation of the MEK/ERK-1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways leading to glucocorticoid unresponsiveness. In primary monocytes, the mechanism involved modulation of histone deacetylase 2 (HDAC2) activity in response to GSK3β inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3β, acting as a ROS-sensitive hub.
Association of Differential Mast Cell Activation with Granulocytic Inflammation in Severe Asthma
Publisher: American Thoracic Society
Date: 15-02-2022
Correction to: Exhaled nitric oxide is not a biomarker for idiopathic pulmonary arterial hypertension or for treatment efficacy
Publisher: Springer Science and Business Media LLC
Date: 05-11-2019
DOI: 10.1186/S12890-019-0984-6
Abstract: Following publication of the original article [1], the authors flagged that name of the author ‘Batoul Khoundabi’ had been provided with an incorrect spelling: ‘Batoutl’ was given in place of ‘Batoul’.
Clinical Definition of COPD Exacerbations and Classification of Their Severity
Publisher: Southern Medical Association
Date: 03-2009
Tumour Necrosis Factor α Causes Retention of Activated Glucocorticoid Receptor within the Cytoplasm of A549 Cells
Publisher: Elsevier BV
Date: 08-1996
Abstract: Glucocorticosteroids are the most effective therapy for the suppression of airway inflammation. Classically, ligand binding to the inactive cytosolic receptor (GR) causes a conformational change enabling nuclear translocation of the active GR and alteration in the transcriptional response. We have investigated GR-transcription factor interactions within the cytoplasm where many transcription factors are localized prior to activation. Active DNA binding GR complexes were found within the cytoplasm of human lung epithelial cells (A549). Stimulation by dexamethasone (1 microM) caused translocation of active GR into the nucleus and inhibition of RANTES release. Coincubation of cells with dexamethasone and TNF alpha (1 ng/ml) or PMA (0.1 microM) prevented RANTES release and the translocation of activated GR to the nucleus without affecting GR levels as detected by western blotting. These results suggest that a major site of pro-inflammatory cytokine action may be within the cytoplasm of steroid-responsive cells acting via prevention of the GR translocation into the nucleus.
Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease
Publisher: Elsevier BV
Date: 09-2018
Weighted Gene Co-expression Network Analysis of blood paediatric samples from the U-BIOPRED study identifies oxidative stress association with asthma severity
Publisher: European Respiratory Society
Date: 15-09-2018
Topological data analysis (TDA) of U-BIOPRED paediatric peripheral blood gene expression identified asthma phenotypes characterised by alternative splicing of glucocorticoid receptor (GR) mRNA
Publisher: European Respiratory Society
Date: 15-09-2018
Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease
Publisher: American Thoracic Society
Date: 05-2012
Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies
Publisher: European Respiratory Society (ERS)
Date: 09-2001
DOI: 10.1183/09031936.01.00040701
Abstract: GATA-binding proteins are a subfamily of zinc finger transcription factors with six members (GATA-1-6) that interact with the GATA deoxyribonucleic acid (DNA) sequence. This sequence is found in the regulatory regions of many genes including those encoding T-helper 2 (Th2)-like cytokines, receptors, adhesion molecules and enzymes, which may be important in the pathogenesis of bronchial asthma. The expression of GATA-3, -4 and -6 was investigated in peripheral blood T-lymphocytes and monocytes and bronchial biopsies from 11 normal subjects and 10 steroid-naïve asthmatic patients. Using Western blot analysis, T-cells from asthmatic subjects expressed 5 times the level of GATA-3 compared to that in normals. Confocal microscopy indicated that GATA-3 expression was both nuclear and cytoplasmic. GATA DNA binding complex containing GATA-3 was elevated in Th2 cells as determined by electrophorectic mobility shift assay. In contrast, monocytes from normal and asthmatic subjects expressed GATA-4 and -6 in equal amounts, but no GATA-3 was found. Using immunohistochemistry in bronchial biopsies, epithelial cells expressed high levels of GATA-3, GATA-4 and GATA-6 proteins. Comparison of Western blots of bronchial biopsies showed no significant differences between normal and asthmatic subjects. In conclusion, the increased expression of GATA-3 in asthmatic T-cells may underlie augmented T-helper 2-like cytokines in this disease. However, the unaltered GATA-3 expression in epithelial cells suggests a distinct role for GATA-3 in these cells unrelated to T-helper 2-like cytokine release. Finally, no evidence was found for an increased expression of GATA-4 and GATA-6 in asthma.
CORTICOSTEROIDS | Glucocorticoid Receptors
Publisher: Elsevier
Date: 2006
Instability of sputum molecular phenotypes in U-BIOPRED severe asthma
Publisher: European Respiratory Society (ERS)
Date: 02-10-2020
Langerin-expressing dendritic cells in pulmonary immune-related diseases
Publisher: Frontiers Media SA
Date: 07-09-2022
Abstract: Dendritic cells (DCs) are “frontline” immune cells dedicated to antigen presentation. They serve as an important bridge connecting innate and adaptive immunity, and express various receptors for antigen capture. DCs are ided into various subclasses according to their differential expression of cell surface receptors and different subclasses of DCs exhibit specific immunological characteristics. Exploring the common features of each sub-category has became the focus of many studies. There are certain amounts of DCs expressing langerin in airways and peripheral lungs while the precise mechanism by which langerin + DCs drive pulmonary disease is unclear. Langerin-expressing DCs can be further sub ided into numerous subtypes based on the co-expressed receptors, but here, we identify commonalities across these subtypes that point to the major role of langerin. Better understanding is required to clarify key disease pathways and determine potential new therapeutic approaches.
Clinical and transcriptomic features of persistent exacerbation‐prone severe asthma in U‐BIOPRED cohort
Publisher: Wiley
Date: 04-2022
DOI: 10.1002/CTM2.816
Abstract: Exacerbation‐prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U‐BIOPRED cohort. We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures. Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short‐acting beta‐agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short‐acting beta‐agonist use and asthma control index. CEA cell adhesion molecule 5 ( CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T‐helper type‐17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE. The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively.
Female sex hormones affect asthma severity by altering cellular metabolism in the airways
Publisher: European Respiratory Society
Date: 04-09-2022
Composite type-2 biomarker strategy versus a symptom–risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controll
Publisher: Elsevier BV
Date: 2021
Phosphatidylinositol 3-kinase isoforms as targets in respiratory disease
Publisher: SAGE Publications
Date: 05-01-2010
Abstract: Respiratory diseases such as chronic obstructive pulmonary disease [COPD], severe asthma, cystic fibrosis [CF] and idiopathic pulmonary fibrosis [IPF] are inadequately controlled by current therapies. The underlying molecular mechanisms and pathogenesis of these diseases remain unclear, making identification and validation of potential new therapeutic targets difficult. However, recent studies have identified the central signalling mediator PI3K as playing an integral role in the immune system including initiation and maintenance of inflammatory responses. Specifically, the relatively leukocyte-specific PI3Kγ and PI3Kδ isoforms are central to leukocyte function and can be targeted pharmacologically. Early to man studies using selective PI3K isoform inhibitors are required to determine whether they have a future in treating respiratory disease, particularly in controlling both innate and adaptive inflammatory responses as well as restoring glucocorticoid function and reducing tumorigenesis.
Molecular Mechanisms of Respiratory Virus-Induced Asthma and COPD Exacerbations and Pneumonia
Publisher: Bentham Science Publishers Ltd.
Date: 08-2006
DOI: 10.2174/092986706777935159
Abstract: Lower airways inflammation is a central feature of many lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and pneumonia. Although the specific characteristics of the inflammatory responses and the site of inflammation differ between one disease to another, they always involve recruitment and activation of inflammatory cells and changes in structural cells of the lung. Inflammatory responses are associated with an increased expression of a cascade of proteins including cytokines, chemokines, growth factors, enzymes, adhesion molecules and receptors. In most cases the increased expression of these proteins is the result of enhanced gene transcription: many of these genes are not expressed in normal cells under resting conditions but they are induced in the inflammatory process in a cell-specific manner. Transcription factors regulate the expression of many pro-inflammatory genes and play a key role in the pathogenesis of airway inflammation. Many studies have suggested a role for viral infections not only as a causative agent of pneumonia but also of asthma and COPD exacerbations. In this review we will provide an overview of the relationship between common respiratory viral infections and the molecular mechanisms involved in the activation of airway inflammation and on the regulation of transcription factors in these inflammatory respiratory diseases. The relative importance of each transcription factor will be certainly greatly clarified in the next few years with the growing availability of specific inhibitors capable of blocking activation of a specific transcription factor. Clearly this is an exciting new area of ongoing research with promising therapeutic potential.
The Role of Mast Cells in IgE-Independent Lung Diseases
Publisher: Springer Science and Business Media LLC
Date: 21-02-2020
DOI: 10.1007/S12016-020-08779-5
Abstract: Mast cells (MCs) are granular cells of the innate immune system which develop from CD34 + /CD117 + progenitors and play a role in orchestrating adaptive immune responses. They have a well-known role in allergic reactions following immunoglobulin (Ig)E-mediated activation of the cell-surface expressed IgE high-affinity receptor (FcεRI). MCs can also respond to various other stimuli due to the expression of a variety of receptors including toll-like receptors (TLRs), immunoglobulin (IgG) receptors (FcγR), complement receptors such as C5a (CD88) expressed by skin MCs, neuropeptides receptors including nerve growth factor receptor, (NGFR), cytokines receptors such as (IL)-1R and IL-3R, and chemokines receptors including CCR-1 and CCR-3. MCs release three groups of mediators upon degranulation differentiated according to their chemical composition, storage, and time to release. These include preformed mediators (mainly histamine, tryptase, and chymase), de novo synthesized mediators such as prostaglandin (PG)D2, leukotriene (LT)B4 and LTD4, and cytokines including IL-1β, IL-3, tumor necrosis factor (TNF)α, and transforming growth factor(TGF)-β. Emerging evidence indicates a role for IgE-independent MC activation in the late-stage asthmatic response as well as in non-allergic airway diseases including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. MC infiltration/activation has been reported in some, but not all, studies of lung cancer. MC-derived TNF-α possesses tumor-suppressive activity while IL-1β supports tumor progression and metastasis. In IPF lungs, an increase in density of tryptase- and chymase-positive MCs (MCTC) and overexpression of TGF-β support the fibrosis progression. MC-derived chymase activates latent TGF-β that induces the differentiation of fibroblasts to matrix-producing myofibroblasts. In summary, increasing evidence highlights a critical role of MCs in non-allergic diseases that may indicate new approaches for therapy.
Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism
Publisher: American Physiological Society
Date: 15-06-2015
DOI: 10.1152/AJPLUNG.00220.2014
Abstract: Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione- S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H 2 O 2 ), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H 2 O 2 /HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD + /NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.
Chronic Obstructive Pulmonary Disease and Lung Cancer: A Lethal Association
Publisher: American Thoracic Society
Date: 15-10-2011
Common features of tuberculosis and sarcoidosis
Publisher: Medknow
Date: 12-2016
DOI: 10.1016/J.IJMYCO.2016.09.031
Abstract: Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis. Despite the availability of novel therapeutic approaches, TB is considered as one of the leading causes of death due to infectious diseases worldwide. Alveolar macrophages are the first line of defense against M. tuberculosis they ingest and sequester the bacilli within granulomatous structures. Control and resolution of the infection requires activated T lymphocytes as well as Th1 cytokines. There are two forms of TB: active TB and latent TB. Latent TB is a state in which M. tuberculosis survives in the body without causing overt signs and symptoms. People with latent TB are noncontagious. However, M. tuberculosis can become active in the body, multiply, and cause overt TB. Sarcoidosis, on the other hand, is an autoimmune disease of unknown etiology which can affect multiple systems of the body. Nonspecific constitutional symptoms, such as fever, fatigue, malaise, and weight loss, are present in approximately one-third of patients. Chest X-ray usually shows hilar and mediastinal lymphadenopathy. Although the lungs are the most common sites of inflammation, sarcoidosis can also involve other organs, such as the eyes (intraocular and adnexal), skin, lymph nodes, salivary glands, heart, spleen, liver, and the nervous system. Recent investigations have provided further insights into the genetic basis of sarcoidosis and the way genotype determines the clinical presentation and phenotype of patients. Histopathologic features are usually insufficient for diagnosis of sarcoidosis. Diagnosis of sarcoidosis in endemic areas for TB can become a great challenge. Both TB and sarcoidosis are granulomatous diseases TB is characterized by caseating granulomas, whereas sarcoidosis is characterized by noncaseating granulomas. New cases of sarcoidosis are increasingly being diagnosed in areas endemic for TB due to increased orientation of physicians and availability of diagnostic modalities. However, it is often difficult to differentiate sarcoidosis from TB, especially when caseous necrosis is not seen and acid-fast staining is negative in the biopsy specimen of patient with TB. Granulomatous inflammation in sarcoidosis is believed to be caused by the presence of a persistent poorly degradable unknown antigen in combination with a nonresolving host response. M. tuberculosis has been extensively studied as a possible cause of sarcoidosis. Results suggest that granulomas form in the lungs as a result of the immune response to inhaled M. tuberculosis and serve as the central site of host-pathogen interaction during M. tuberculosis infection. M. tuberculosis DNA detection in sarcoidosis s les by traditional polymerase chain reaction (PCR) has been used for the pathological study of sarcoidosis however, it is likely that real time quantitative PCR analysis of specific mRNAs and microRNAs will be necessary as a sensitive, precise, and rapid diagnostic test for detecting trace of TB in Sarcoidosis. In conclusion, diagnosis of sarcoidosis in areas with a high burden of TB poses a significant challenge. Improved diagnostic tests including genetic tests can improve our knowledge and help in distinguishing these two diseases.
MA12.04 Mitochondrial-Related Proteins, PGAM5 and FUNDC1, in COPD-Associated Non-Small Cell Lung Carcinoma
Publisher: Elsevier BV
Date: 2017
Role of Stem Cells in the Pathogenesis of COPD and Pulmonary Emphysema
Publisher: Springer Netherlands
Date: 2012
In vitro effects of water-pipe smoke condensate on the endocytic activity of Type II alveolar epithelial cells (A549) with bacillus Calmette–Guérin
Publisher: Medknow
Date: 12-2016
DOI: 10.1016/J.IJMYCO.2016.09.036
Abstract: Tuberculosis (TB) is a major global health problem and poses immense threats to many populations. The association between tobacco smoke and TB has already been studied. Water-pipe smoking has become an increasing problem not only in Middle Eastern countries but also globally as it is considered by users as being safer than cigarettes. The presence of high levels of toxic substances in water-pipe smoke may be predisposing factors that enhance the incidence of pulmonary disorders in water-pipe smokers. For ex le, uncontrolled macropinocytosis occurs in alveolar epithelial cells following exposure to water-pipe smoke, which may predispose in iduals to pulmonary infection. In this work, we studied the effects of water-pipe condense (WPC) on the internalization of Mycobacterium bovis (bacillus Calmette-Guérin [BCG]) by macropinocytosis in Type II alveolar epithelial cells (A549). A549 cells were treated by WPC (4mg/mL) for 24 h, 48 h, 72 h, and 96 h, respectively. The effect on cell proliferation was studied using a methylthiazolyldiphenyl-tetrazolium bromide (MTT) reduction assay. Cells were exposed to fluorescein isothiocyanate (FITC)-dextran (1mg/mL control) and FITC-BCG (multiplicity of infection, 10) for 20min at 37°C before their collection and the uptake of BCG-FITC was determined by flow cytometry. Similar experiments were performed at 4°C as a control. WPC (4mg/mL) after 72h (1.4±0.2-fold, p<0.05) and 96h (1.6±0.2-fold, p<0.05) hours increased the uptake of BCG-FITC. No effect on BCG-FITC uptake was observed at 24h or 48h. WPC also significantly increased the uptake of FITC-dextran (2.9±0.3-fold, p<0.05) after 96h. WPC also significantly decreased cell proliferation after 24h (84±2%), 48h (78±3%), 72h (64±2%, p<0.05), and 96h (45±2%, p<0.05). WPC exposure increased epithelial cells' permeability and death and enhanced their capacity for macropinocytosis. Our in vitro data suggest possible harmful effects of WPC on the ability of lung epithelial cells to phagocytose mycobacteria. Further studies will be conducted to understand the mechanism of action of WPC.
Effect of an inhibitor of Jun N‐terminal protein kinase, SP600125, in single allergen challenge in sensitized rats
Publisher: Wiley
Date: 17-05-2004
S152 Dexamethasone reverses established monocrotaline-induced pulmonary hypertension in rats and increases pulmonary BMPR2 expression
Publisher: BMJ
Date: 16-11-2010
Drugs for the Treatment of Airway Disease
Publisher: Springer International Publishing
Date: 2019
Role of Transcription Factors in the Pathogenesis of Asthma and COPD
Publisher: Informa UK Limited
Date: 02-2013
DOI: 10.3109/15419061.2013.775257
Abstract: Inflammation is a central feature of asthma and chronic obstructive pulmonary disease (COPD). Despite recent advances in the knowledge of the pathogenesis of asthma and COPD, much more research on the molecular mechanisms of asthma and COPD are needed to aid the logical development of new therapies for these common and important diseases, particularly in COPD where no effective treatments currently exist. In the future the role of the activation/repression of different transcription factors and the genetic regulation of their expression in asthma and COPD may be an increasingly important aspect of research, as this may be one of the critical mechanisms regulating the expression of different clinical phenotypes and their responsiveness to therapy, particularly to anti-inflammatory drugs.
IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JACI.2018.08.051
Abstract: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive. We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral activity, and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33-dependent mechanisms that underlie severe asthma exacerbations. Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti-IL-33 receptor ST2, anti-TSLP, or both. We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite-sensitized mice to d en IFN-β expression and prevent the T Interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy for virus-induced asthma exacerbations.
Effect of interleukin-10 on the production of tumor necrosis factor-alpha by peripheral blood mononuclear cells from patients with chronic heart failure
Publisher: Elsevier BV
Date: 08-2002
DOI: 10.1016/S0002-9149(02)02494-3
Abstract: Chronic heart failure (HF) is a state of inflammatory immune activation characterized by elevated circulating levels of tumor necrosis factor-alpha (TNF-alpha). Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that inhibits TNF-alpha production and lessens endotoxin bioactivity. It is not known whether IL-10 reduces lipopolysaccharide (LPS) stimulated TNF-alpha production of peripheral blood mononuclear cells (PBMCs) from patients with chronic HF. PBMCs were isolated from 15 patients with chronic HF (New York Heart Association functional class 3.0 +/- 0.2, left ventricular ejection fraction 30 +/- 2%, peak oxygen consumption 18.1 +/- 0.8 ml/kg/min) and 15 healthy control subjects and stimulated with 1 and 10 ng/ml LPS for 24 hours with or without prior addition of IL-10 (10 ng/ml). TNF-alpha was quantified in cell-free supernatants by an enzyme-linked immunosorbent assay. TNF-alpha, soluble TNF receptors, IL-10, and LPS were quantified in plasma. LPS stimulated TNF-alpha production was highest in those patients in New York Heart Association class II (p <0.01 vs New York Heart Association class III and IV, p <0.001 vs control subjects). IL-10 reduced PBMC TNF-alpha production in all stimulated s les at 1 and 10 ng/ml LPS (mean reduction 43% at 1 ng/ml, p <0.01 and 55% at 10 ng/ml, p <0.0001). The percentage reduction in TNF-alpha release did not differ significantly between patients and control subjects or with respect to severity of chronic HF or baseline immune parameters. Independently of clinical severity, IL-10 profoundly inhibits TNF-alpha release from PBMCs isolated from patients with chronic HF. IL-10 is, therefore, a potential therapy for use in chronic HF associated with inflammatory immune activation.
Effect of smoking on MAP kinase-induced modulation of IL‐8 in human alveolar macrophages
Publisher: European Respiratory Society (ERS)
Date: 06-2004
DOI: 10.1183/09031936.04.00104304
Abstract: Inflammatory cytokine production by alveolar macrophages (AMs) is regulated by transcriptional activation and may be increased by cigarette smoking. The smoking-induced regulation of interleukin (IL)-8 by extracellular signal-regulated kinase (ERK)-1 and -2, p38 mitogen-activated protein kinase (MAPK) and the transcription factor nuclear factor-kappaB (NF-kappaB) in lipopolysaccharide-stimulated AMs was assessed in nine smokers compared with nine healthy nonsmokers. IL-8 production was dependent on phosphorylation of ERK-1 and -2 and p38 MAPK, as examined by PD 098059 (10 microM), an inhibitor of the upstream activator of MAPK kinase (MKK)-1, and SB 203580 (10 microM), an inhibitor of p38 MAPK. IL-8 release and the inhibitory effect of PD 098059 were increased in AMs from smokers. Moreover, ERK-2 messenger ribonucleic acid expression, as examined by reverse transcriptase polymerase chain reaction and phosphorylation of ERK-2 using Western blots, were increased in AMs from smokers, indicating a smoking-induced modulatory role of ERK-1 and -2. Lipopolysaccharide-induced IL-8 production was dependent on activation of NF-kappaB, as examined by SN 50 (100 microM), an inhibitor of NF-kappaB translocation, and the specific NF-kappaB inhibitor kinase-2 inhibitor, AS 602868 (10 microM), with no differences in AMs from smokers and nonsmokers. SN 50 but not PD 098059 and SB 203580 blocked NF-kappaB deoxyribonucleic acid-binding, and this occurred to the same extent in AMs from smokers and nonsmokers, as examined by electromobility shift assay. It is concluded that cigarette smoking enhances mitogen-activated protein kinase activation more than nuclear factor-kappaB activation to increase lipopolysaccharide-induced interleukin-8 production in alveolar macrophages.
Common Infections and Target Organs Associated with Chronic Granulomatous Disease in Iran
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000496181
Abstract: Recurrent severe bacterial and fungal infections are characteristic features of the rare genetic immunodeficiency disorder chronic granulomatous disease (CGD). The disease usually manifests within the first years of life with an incidence of 1 in approximately 200,000 live births. The incidence is higher in Iran and Morocco where it reaches 1.5 per 100,000 live births. Mutations have been described in the 5 subunits of NADPH oxidase, mostly in gp91 sup hox /sup and p47 sup hox /sup , with fewer mutations reported in p67 sup hox /sup , p22 sup hox /sup , and p40 sup hox /sup . These mutations cause loss of superoxide production in phagocytic cells. i CYBB /i , the gene encoding the large gp91 sup hox /sup subunit of the transmembrane component cytochrome i b /i sub /sub of the NADPH oxidase complex, is localized on the X-chromosome. Genetic defects in i CYBB /i are responsible for the disease in the majority of male CGD patients. CGD is associated with the development of granulomatous reactions in the skin, lungs, bones, and lymph nodes, and chronic infections may be seen in the liver, gastrointestinal tract, brain, and eyes. There is usually a history of repeated infections, including inflammation of the lymph glands, skin infections, and pneumonia. There may also be a persistent runny nose, inflammation of the skin, and inflammation of the mucous membranes of the mouth. Gastrointestinal problems can also occur, including diarrhea, abdominal pain, and perianal abscesses. Infection of the bones, brain abscesses, obstruction of the genitourinary tract and/or gastrointestinal tract due to the formation of granulomatous tissue, and delayed growth are also symptomatic of CGD. The prevention of infectious complications in patients with CGD involves targeted prophylaxis against opportunistic microorganisms such as i Staphylococcus aureus /i , i Klebsiella /i spp., i Salmonella /i spp. and i Aspergillus /i spp. In this review, we provide an update on organ involvement and the association with specific isolated microorganisms in CGD patients.
Targeting Th2 Cells in Asthmatic Airways
Publisher: Bentham Science Publishers Ltd.
Date: 09-2004
Abstract: The most effective anti-asthmatic drugs currently available include inhaled beta2-agonists and glucocorticoids and control asthma in about 95% of patients. The current asthma therapies are not cures and symptoms return soon after the treatment is stopped even after long-term therapy. In addition, severe glucocorticoid-dependent and -resistant asthma still represents a great clinical burden accounting for approximately 50% of the health care costs of asthma and reducing the side-effects of glucocorticoids using novel dissociated steroids, soft steroids or with steroid-sparing agents will prove beneficial. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Hopefully, it will soon be possible to identify and manipulate the molecular switches that result in asthmatic inflammation. This may lead to the treatment of susceptible in iduals at birth or in the early years and thus prevent the disease from becoming established. Drug development for asthma has been directed at improving currently available drugs and finding new compounds that usually target the Th2-driven airway inflammatory response. Several new drugs have been developed to target specific components of the Th2-driven inflammatory process in asthma (e.g. IgE antibodies, cytokines and/or chemokines, immunomodulators, antagonists of adhesion molecules), although they have not yet been proven to be particularly effective. Some of these new Th2-oriented strategies may in the future not only control symptoms, but also potentially prevent or cure the disease.
Inflammasome Signaling in Pathogenesis of Lung Diseases
Publisher: Bentham Science Publishers Ltd.
Date: 04-2012
DOI: 10.2174/138161212800166077
Abstract: Asthma and Chronic Obstructive Pulmonary Disease (COPD) are two important lung and airways diseases which affect the lives of ∼500 million people worldwide. Asthma is a heterogeneous disease that is broadly defined as a clinical syndrome characterized by altered lung function, mucus hypersecretion, peribronchial inflammation and hyperresponsiveness In contrast, the effect of inhalation of toxic particles and gases on the innate and adaptive inflammatory immune systems underlie the pathogenesis of COPD. In the last decade, knowledge concerning the pathophysiologic mechanisms underlying asthma and COPD has risen tremendously and current dogma suggests that the pathogenesis of both diseases is driven by the chronic inflammation present in the airways of these patients. Thus, understanding the mechanisms for the persistence of inflammation may lead to new therapeutic approaches. In this review, we provide an overview of the main signal transduction pathways implicated in asthma and COPD pathophysiology focusing on inflammasome signaling in various cells types which result in altered inflammatory mediator expression.
Correction to: Is diet partly responsible for differences in COVID-19 death rates between and within countries?
Publisher: Wiley
Date: 26-10-2020
DOI: 10.1186/S13601-020-00351-W
Abstract: An amendment to this paper has been published and can be accessed via the original article.
Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies
Publisher: Wiley
Date: 12-2020
DOI: 10.1186/S13601-020-00362-7
Abstract: There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT 1 R axis (AT 1 R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.
The effect of oxidative stress on histone acetylation and IL-8 release
Publisher: Elsevier BV
Date: 02-2003
DOI: 10.1016/S0006-291X(02)03029-2
Abstract: Acetylation of histone residues regulates the expression of inflammatory genes and is controlled by the activities of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Analysis of histone acetylation in human cells is limited by the large numbers needed to perform activity assays or Western blotting. We have used flow cytometry to investigate changes in HAT and HDAC activities at the single cell level and to investigate the effect of hydrogen peroxide (H(2)O(2)) on histone H4 acetylation and cell-cycle progression. Using an anti-acetylated histone H4 antibody we show that H(2)O(2) induced a time-dependent increase in histone acetylation that was maintained for 12h. This was associated with increased IL-8 production. H(2)O(2) also affected cell-cycle progression. HAT activity was found to be highest in G2/M and equivalent in G0/G1 and S phases of the cell cycle. These data show that detection of acetylated histone residues at the single cell level using FACs may be a powerful new tool for the analysis of modulation of cell proliferation and gene transcription.
The miR-146a SNP Rs2910164 and miR-155 SNP rs767649 Are Risk Factors for Non-Small Cell Lung Cancer in the Iranian Population
Publisher: Hindawi Limited
Date: 20-11-2020
DOI: 10.1155/2020/8179415
Abstract: Background. Lung cancer is one of the leading causes of death worldwide. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and may act as both tumor suppressors and as oncogenes. The presence of single nucleotide polymorphisms (SNPs) inside the miRNA genomic region could affect target miRNA maturation, expression, and binding to its target mRNA and contribute to cancer development. Previous studies on the SNPs Rs2910164 in miR-146a and Rs767649 in miR-155 showed association with non-small cell lung cancer (NSCLC) development. Thus, the aim of this study was to detect any correlation between those SNPs in Iranian NSCLC patients. Methods. In a small cohort study, 165 NSCLC patients and 147 noncancer controls were enrolled between Apr 2015 and Sep 2019 at the Masih Daneshvari Hospital, Tehran, Iran. Allele frequencies from the genomic DNA of blood cells were studied using PCR-RFLP and their association with the risk of lung cancer was evaluated. Results. The rs2910164C allele (OR = 1.56, 95% CI = 1.10–2.21, p = 0.012 ) and CC genotype (OR = 2.93, 95% CI = 1.07–7.9, p = 0.034 , respectively) were associated with a significantly increased risk for lung cancer compared to that for the GG genotype. When patients were stratified according to smoking exposure, no association with rs2910164 variants was found. The AT genotype (OR = 0.57, 95% CI = 0.33–0.99, p = 0.048 ) and the A allele frequency (OR = 0.58, 95% CI = 0.35–0.98, p = 0.043 ) in rs767649 were lower in NSCLC patients in comparison with the control group. In addition, the rs767649 AT genotype frequency in smoking controls was higher than in smoking NSCLC patients (OR = 0.44, 95% CI = 0.21–0.90, p = 0.024 ). No association was found between rs2910164 and rs767649 variants and stage or type of NSCLC. Conclusion. Our finding suggests that miR-146a rs2910164 and miR-155 rs767649 polymorphisms may be considered as genetic risk factors for the susceptibility to NSCLC in the Iranian population. However, a larger multicenter study across Iran is needed to confirm these findings.
Increased expression of nuclear factor- B in bronchial biopsies from smokers and patients with COPD
Publisher: European Respiratory Society (ERS)
Date: 09-2002
DOI: 10.1183/09031936.02.00272002
Abstract: The expression of nuclear factor (NF)-kappaB is an indicator of cellular activation and of inflammatory mediator production. The aim of the present study was to characterise the expression and localisation of p65, the major subunit of NF-kappaB, in the bronchial mucosa of patients with chronic obstructive pulmonary disease (COPD), and to examine the relationship between p65 expression and disease status. Bronchial biopsies were obtained from 14 smokers with COPD, 17 smokers with normal lung function and 12 nonsmokers with normal lung function. The number of p65 positive (+) cells was quantified by immunohistochemistry and the expression of p65 in bronchial biopsies from the three groups was examined by Western blotting (WB). Smokers with normal lung function and patients with COPD had increased numbers of p65+ cells in the epithelium and increased p65 nuclear expression. In COPD patients the number of epithelial p65+ cells correlated with the degree of airflow limitation. WB analysis showed an increase in p65 in smokers with normal lung function and COPD patients (p<0.05). Bronchial biopsies in smokers with normal lung function and chronic obstructive pulmonary disease patients show increased expression of p65 protein, predominantly in the bronchial epithelium. Disease severity is associated with an increased epithelial expression of nuclear factor-kappaB.
NF-κB involvement in IL-1β-induction of GM-CSF and COX-2: inhibition by glucocorticoids does not require I-κB
Publisher: Portland Press Ltd.
Date: 05-1997
DOI: 10.1042/BST025154S
Abstract: The S100/calgranulin gene appears to modulate neuroinflammation following cerebral ischemia and could be a valuable biomarker for stroke prognosis, according to growing research. This study aimed at evaluating the correlation between calgranulin gene variants and susceptibility to ischemic stroke (IS) in the Southern Chinese population. Using an enhanced multi-temperature ligase detection reaction genotyping, 310 IS patients and 324 age-matched healthy controls were genotyped to identify five calgranulin gene variants. According to the obtained results, the S100A8 rs3795391, rs3806232, and S100A12 rs2916191 variants were linked to a higher risk of IS, while the S100A9 rs3014866 variant was associated with a lower risk of IS. Moreover, the T-T-C-A-T, T-T-C-G-T, or C-C-C-G-C haplotypes have been linked to a greater risk of developing IS, according to haplotype analysis. The occurrence of the variant C allele there in S100A8 rs3795391, rs3806232, and S100A12 rs2916191 variants may impart a greater risk of stroke in the LAA subtype, according to further stratification by IS subtypes, while the T allele of the S100A9 rs3014866 variant may be linked to a reduced risk of stroke of all subtypes. Furthermore, patients with the variant C allele of the S100A8 rs3795391, rs3806232, and S100A12 rs2916191 variants presented with increased circulating S100A8 and S100A12 levels and larger infarct volumes relative to those with the major TT genotype. Our findings suggest that calgranulin gene variants are linked to IS susceptibility, implying that the calgranulin gene may be a potential biomarker for IS prevention and personalized treatment.
Evaluation of inflammatory mediators of pleural effusion in tuberculosis and non-tuberculosis patients
Publisher: European Respiratory Society
Date: 07-09-2020
Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease
Publisher: American Thoracic Society
Date: 10-2011
The carnitine pathway is dysregulated in asthma in an oral corticosteroid-independent mechanism
Publisher: European Respiratory Society
Date: 05-09-2021
Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction
Publisher: European Respiratory Society (ERS)
Date: 05-03-2008
DOI: 10.1183/09031936.00018908
Abstract: Chronic obstructive pulmonary disease is a leading global cause of morbidity and mortality that is characterised by inexorable deterioration of small airways obstruction with emphysema associated with cellular inflammation and structural remodelling. Other features include apoptosis as well as proliferation of cells, and both tissue repair and lack of tissue repair. Metalloprotease release, together with that of apoptotic factors, may underlie the emphysema, and, conversely, fibrosis of the small airways may be accounted for by the effects of growth factor activation. In advanced disease, influential factors include the development of autoimmunity, with activation of dendritic cells and T-helper cells of both type 1 and 2, and the senescence response. An inability of macrophages to ingest apoptosed cells and bacteria may exacerbate inflammatory responses. Systemic inflammation with concomitant cardiovascular disease and metabolic syndrome may reflect the effect of cigarette smoke on nonpulmonary cells. Corticosteroid resistance may be secondary to oxidative stress mechanisms, such as inactivation of histone deacetylases. The mechanisms of chronic obstructive pulmonary disease may be heterogeneous, according to severity, and clinical phenotypes need to be correlated with cellular and pathological processes. Treatments may be targeted to patients with specific mechanisms.
Evaluation of Th9 and Th22 cells within pleural effusions of tuberculosis and non-tuberculosis patients
Publisher: European Respiratory Society
Date: 07-09-2020
[50] Induction of nuclear factor-κB by exposure to ozone and inhibition by glucocorticoids
Publisher: Elsevier
Date: 2000
Urinary Leukotriene E4and Prostaglandin D2Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study
Publisher: American Thoracic Society
Date: 2021
Anti-Inflammatory Effects of Lactobacillus Rahmnosus and Bifidobacterium Breve on Cigarette Smoke Activated Human Macrophages
Publisher: Public Library of Science (PLoS)
Date: 28-08-2015
Mechanistic qualities of steroids in chronic–severe asthma
Publisher: Wiley
Date: 06-2001
STAT4 activation in smokers and patients with chronic obstructive pulmonary disease
Publisher: European Respiratory Society (ERS)
Date: 07-2004
DOI: 10.1183/09031936.04.00080303
Abstract: Activation of the transcription factor signal transducer and activator of transcription (STAT)-4 is critical for the differentiation of T-helper 1 cells/type-1 cytotoxic T-cells and the production of interferon (IFN)-gamma. Expression of STAT4, phospho-STAT4, IFN-gamma and T-box expressed in T-cells (T-bet) proteins in bronchial biopsies and bronchoalveolar lavage (BAL)-derived lymphocytes, obtained from 12 smokers with mild/moderate chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) 59 +/- 16% predicted), 14 smokers with normal lung function (FEV1 106 +/- 12% pred) and 12 nonsmoking subjects (FEV1 111 +/- 14% pred), was examined by immunohistochemistry and immunocytochemistry. In bronchial biopsies of COPD patients, the number of submucosal phospho-STAT4+ cells was increased (240 (22-406) versus 125 (0-492) versus 29 (0-511) cells mm(-2)) when compared with both healthy smokers and control nonsmokers, respectively. In smokers, phospho-STAT4+ cells correlated with the degree of airflow obstruction and the number of IFN-gamma+ cells. Similar results were seen in BAL (2.8 (0.2-5.9) versus 1.03 (0.09-1.6) versus 0.69 (0-2.3) lymphocytes x mL(-1) x 10(3)). In all smokers who underwent lavage, phospho-STAT4+ lymphocytes correlated with airflow obstruction and the number of IFNgamma+ lymphocytes. T-bet expression was not altered in bronchial biopsies and BAL-derived lymphocytes between the three groups. In conclusion, this study suggests that stable mild/moderate chronic obstructive pulmonary disease is associated with an active T-helper 1 cell/type-1 cytotoxic T-cell inflammatory process involving activation of signal transducer and activator of transcription 4 and interferon-gamma production.
TRANSCRIPTION FACTORS | Overview
Publisher: Elsevier
Date: 2006
Characteristics and treatment regimens across ERS SHARP severe asthma registries
Publisher: European Respiratory Society
Date: 28-09-2019
Glucocorticoid Receptor Recruitment of Histone Deacetylase 2 Inhibits Interleukin-1β-Induced Histone H4 Acetylation on Lysines 8 and 12
Publisher: Informa UK Limited
Date: 09-2000
New Insights into the Molecular Mechanisms of Corticosteroids Actions
Publisher: Bentham Science Publishers Ltd.
Date: 06-2006
DOI: 10.2174/138945006777435344
Abstract: Corticosteroids produce a marked improvement in clinical parameters in most asthmatic patients in contrast, corticosteroids have little effect on lung function measurements in patients with chronic obstructive pulmonary disease. By uncovering the reason for this paradox, it should be possible to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic receptor, which is subjected to post-translational modifications. Receptor phosphorylation may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Other modifications such as nitration/nitrosylation may also affect glucocorticoid receptor function. Oxidative stress due to cigarette smoke may be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription and reduces glucocorticoid receptor-associated repressor functions. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.
Heightened response to e-cigarettes in COPD.
Publisher: European Respiratory Society (ERS)
Date: 02-2019
Up-regulation of blood arachidonate (20:4) levels in patients with chronic obstructive pulmonary disease
Publisher: Informa UK Limited
Date: 30-05-2012
Probiotics in the Management of Lung Diseases
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/751068
Abstract: The physiology and pathology of the respiratory and gastrointestinal tracts are closely related. This similarity between the two organs may underlie why dysfunction in one organ may induce illness in the other. For ex le, smoking is a major risk factor for COPD and IBD and increases the risk of developing Crohn’s disease. Probiotics have been defined as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host.” In model systems probiotics regulate innate and inflammatory immune responses. Commonly used probiotics include lactic acid bacteria, particularly Lactobacillus , Bifidobacterium , and Saccharomyces , and these are often used as dietary supplements to provide a health benefit in gastrointestinal diseases including infections, inflammatory bowel disease, and colon cancer. In this respect, probiotics probably act as immunomodulatory agents and activators of host defence pathways which suggest that they could influence disease severity and incidence at sites distal to the gut. There is increasing evidence that orally delivered probiotics are able to regulate immune responses in the respiratory system. This review provides an overview of the possible role of probiotics and their mechanisms of action in the prevention and treatment of respiratory diseases.
Low‐dose theophylline does not exert its anti‐inflammatory effects in mild asthma through upregulation of interleukin‐10 in alveolar macrophages
Publisher: Wiley
Date: 11-2001
DOI: 10.1034/J.1398-9995.2001.00097.X
Abstract: There is accumulating evidence that theophylline has anti-inflammatory or immunomodulatory effects. This may be, in part, mediated via an upregulation in the production of the anti-inflammatory cytokine interleukin (IL)-10. We determined whether low-dose theophylline (LDT) would increase the production of IL-10, and attenuate the production of proinflammatory cytokines by alveolar macrophages. In a double-blind, placebo-controlled, crossover study involving 15 steroid-free patients with mild asthma, fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed at the end of the treatment and placebo periods. Alveolar macrophages were cultured in vitro, and we measured their release of IL-10, GM-CSF, and TNF-alpha. We also measured IL-10 production in whole blood together with the number of monocytes and T cells expressing intracellular IL-10 by flow cytometry. LDT did not increase the production of IL-10, or attenuate the production of GM-CSF or TNF-alpha by alveolar macrophages. However, after theophylline treatment, there was a significant reduction in mean (SD) (95% CI) BAL eosinophil number from 3.4 (1.7)% (95% CI 2.4-4.4) to 1.7 (1.0)% (95% CI 1.1-2.3) compared with placebo (P<0.05). Similarly, there was no increase in whole-blood IL-10 release or in the number of monocytes and T cells expressing intracellular IL-10 after treatment. LDT has an anti-inflammatory effect in asthma however, this effect is not mediated via the production of IL-10 or the attenuation of GM-CSF or TNF-alpha. The mechanisms of theophylline activity remain to be determined.
Silent hypoxia: higher NO in red blood cells of COVID-19 patients
Publisher: Springer Science and Business Media LLC
Date: 16-10-2020
DOI: 10.1186/S12890-020-01310-8
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 31 M patients and resulted in 961 K deaths worldwide as of 21st September 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute respiratory distress syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia is seen in the COVID-19 patients, however, patients present with a distinct phenotype. Intracellular levels of nitric oxide (NO) play an important role in the vasodilation of small vessels. To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects. We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 non-COVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March–May 2020. Whole blood s les were harvested from patients and intracellular NO levels in 1 × 10 6 red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA). The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects ( P ≤ 0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group. This pilot study demonstrates increased levels of intracellular NO in RBCs from COVID-19 patients. Future multi-centre studies should examine whether this is seen in a larger number of COVID-19 patients and whether NO therapy may be of use in these severe COVID-19 patients.
Epigenetic Regulation of Asthma and Allergic Diseases
Publisher: Springer London
Date: 2011
Glucocorticoid-regulated Transcription Factors
Publisher: Elsevier BV
Date: 06-2001
Brd4 Is Essential for IL-1β-Induced Inflammation in Human Airway Epithelial Cells
Publisher: Public Library of Science (PLoS)
Date: 23-04-2014
Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JACI.2013.07.038
Abstract: Combination inhaled therapy with long-acting β2 agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD). In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain. Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 μg, FP 500 μg, salmeterol xinafoate (SLM) 50 μg, and combination FP 100 μg + SLM 50 μg. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR-glucocorticoid response element ELISA-based assay. Nuclear GR significantly increased after the inhalation of FP 500 μg (P < .01), but not after the inhalation of FP 100 μg or SLM 50 μg, compared with placebo. Interestingly, SLM in combination with FP 100 μg increased nuclear GR levels equivalent to those of FP 500 μg alone. This was significantly greater than either FP 100 μg (P < .05) or SLM 50 μg (P < .01) alone. In vitro in a human macrophage cell line, SLM (10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 ± 0.6 vs 8.4 ± 1.1 × 10(-6) copies, P < .05) and 2 × glucocorticoid response element-luciferase reporter gene activity (250.1 ± 15.6 vs 103.1 ± 23.6-fold induction, P < .001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1β-induced CXCL8 (P < .05). Addition of SLM 50 μg to FP 100 μg enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD.
Molecular interactions between glucocorticoids and long-acting β2-agonists
Publisher: Elsevier BV
Date: 12-2002
Abstract: beta(2)-Adrenergic receptor agonists and glucocorticoids are the two most effective treatments for asthma, and used in combination they are more effective than either alone. Glucocorticoids mediate their anti-inflammatory effects through the action of activated glucocorticoid receptors (GRs), with the level of activity being related to the number of nuclear receptors. Glucocorticoids can upregulate the synthesis of several genes in human lung cells through interaction with specific DNA binding regions (glucocorticoid response elements) within the promoter region of glucocorticoid-responsive genes. Many of the down-regulating effects of GRs on the synthesis of cytokines and other inflammatory mediators are due to repression of other transcription factors, such as activator protein-1 and nuclear factor kappaB. GR functions such as nuclear localization and gene activation can be regulated by phosphorylation status. Long-acting beta(2)-agonists may affect GR nuclear localization through modulation of GR phosphorylation and furthermore through priming of GR functions within the nucleus by modifying GR or GR-associated protein phosphorylation. Glucocorticoids in turn may regulate beta(2)-adrenergic receptor function by increasing its expression, acting through glucocorticoid response elements, and, importantly, by restoring G-protein-beta(2)-receptor coupling and inhibiting beta(2)-receptor downregulation, thereby preventing desensitization.
Decreased T lymphocyte infiltration in bronchial biopsies of subjects with severe chronic obstructive pulmonary disease
Publisher: Wiley
Date: 06-2001
DOI: 10.1046/J.1365-2222.2001.01098.X
Abstract: Studies on the inflammatory process in the large airways of patients with mild/moderate COPD have shown a prevalent T lymphocyte and macrophage infiltration of the bronchial mucosa. However, bronchial inflammation in more severe disease has not been extensively studied. The aim of the present study was to characterize the lymphocyte infiltration in the bronchial mucosa of subjects with severe, compared to mild, COPD, and to examine the relationship between airflow limitation and T lymphocyte numbers in the bronchial mucosa. We examined bronchial biopsies obtained from nine smokers with severe airflow limitation, nine smokers with mild/moderate airflow limitation and 14 smokers with normal lung function. Immunohistochemical methods on cryostat sections were used to assess the number of CD3+, CD4+, CD8+ cells and the number of CD3+ cells coexpressing the chemokine receptor CCR5 (CCR5+CD3+) in the subepithelium. Subjects with severe COPD had lower numbers of CD3+, CD8+ and CCR5+CD3+ cells than mild/moderate COPD (P < 0.012, P < 0.02 and P < 0.02, respectively) and control smokers (P < 0.015, P < 0.005 and P < 0.015, respectively). In subjects with airflow limitation the number of CD3+ and CD8+ cells was inversely correlated with the degree of airway obstruction (r = 0.59, P < 0.015 and r = 0.52, P < 0.032, respectively). Bronchial inflammation in severe COPD is characterized by lower numbers of CD3+ and CD8+ cells and decreased numbers of CD3+ cells coexpressing the chemokine receptor CCR5. T lymphocyte infiltration is inversely correlated with the degree of airflow limitation.
Overcoming steroid unresponsiveness in airways disease
Publisher: Portland Press Ltd.
Date: 22-07-2009
DOI: 10.1042/BST0370824
Abstract: Most of the patients with asthma are found to be successfully treated with conventional therapy. However, there are a small proportion of asthmatic patients who fail to respond to corticosteroids even at high doses or with supplementary therapy. In addition, even high doses of corticosteroids have a minimal effect on the inexorable decline in lung function in COPD (chronic obstructive pulmonary disease) and only a small effect in reducing exacerbations. Corticosteroid-insensitivity therefore presents a profound management problem. Corticosteroids act through a cytosolic receptor [GR (glucocorticoid receptor)], which is activated and translocates to the nucleus. Once in the nucleus, it either binds to DNA and switches on the expression of anti-inflammatory genes or represses the activity of distinct signalling pathways such as NF-κB (nuclear factor κB), AP-1 (activator protein-1) or MAPKs (mitogen-activated protein kinases). This latter step requires the recruitment of co-repressor molecules. A failure to respond to corticosteroids may therefore result from lack of binding to GR, reduced GR expression, lack of co-repressor activity or enhanced activation of inflammatory pathways. These events can be modulated by oxidative stress or high levels of inflammatory cytokines, which may lead to a reduced clinical outcome. Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new anti-inflammatory drugs or reverse the relative corticosteroid-insensitivity that is characteristic of these diseases.
Activation and Localization of Transcription Factor, Nuclear Factor- κ B, in Asthma
Publisher: American Thoracic Society
Date: 11-1998
DOI: 10.1164/AJRCCM.158.5.9706116
Abstract: Asthma is associated with increased expression of inflammatory proteins including cytokines, enzymes, and adhesion molecules. Induction of many of the genes for these proteins is regulated by the transcription factor, nuclear factor-kappaB (NF-kappaB). We therefore examined whether airway cells from patients with asthma show increased activation of NF-kappaB. Nuclear proteins were extracted from cells of induced sputum and from bronchial biopsies of normal subjects and patients with asthma. NF-kappaB-binding to its consensus DNA binding site, as investigated with 32P-labeled oligonucleotides and electrophoretic-mobility-shift assay, showed a 2.5-fold increase (p < 0.003) in NF-kappaB-DNA binding in induced sputum of asthma patients. Nuclear staining, representing activated NF-kappaB, was observed in macrophages of induced sputum. Immunohistochemical examination of bronchial biopsy specimens with an antibody to p65, a constituent of NF-kappaB, showed more airway epithelial cells with nuclear staining in asthma patients (45.1 +/- 7.2% versus 20.7 +/- 3.9% n = 9 p < 0.01), and a 2.5-fold greater number of cells with cytoplasmic staining in the mucosal region (p < 0.05). Pooled nuclear extracts of bronchial biopsy specimens from asthma patients showed a 44% greater level of NF-kappaB-DNA binding. Activation of NF-kappaB may be the basis for increased expression of many inflammatory genes and for the perpetuation of chronic airway inflammation in asthma.
Rescue Treatment in Asthma
Publisher: Elsevier BV
Date: 06-2009
Abstract: International guidelines recommend the use of rapid-onset inhaled beta(2)-agonists alone for symptom relief in all asthmatic patients. However, recent clinical trials have shown that the "as-required," or PRN, use of inhaled combinations of a corticosteroid and a rapid-onset beta(2)-agonist provides clinical advantages over the traditional PRN inhaled rapid-onset beta(2)-agonists alone in patients with different degrees of asthma severity. Asthma symptoms are associated not only with bronchoconstriction but also with increased airway inflammation. Inhaled beta(2)-agonists have a rapid onset of bronchodilator action that is mainly mediated by a relaxing effect on airway smooth muscle. Inhaled corticosteroids also have rapid clinical effects that can suppress lower airway inflammation, and there is a rapid synergistic potentiation of the antiinflammatory effect of corticosteroids and of the bronchodilatory action of beta(2)-agonists when the two drugs are given simultaneously. On the basis of this emerging evidence, we propose that the current rescue use of rapid-onset inhaled beta(2)-agonists alone should now be replaced by an inhaled rapid-acting beta(2)-agonist combined with a corticosteroid as preferred PRN strategy. We conclude with a call for clinical trials aimed to test the superiority of this approach in all degrees of asthma severity in a real-world setting in addition to any of the regular treatments recommended by international guidelines. In the future it might even be possible to control asthma entirely with PRN combination inhalers without maintenance therapy, at least in patients with less severe disease.
HDAC inhibitors as anti‐inflammatory agents
Publisher: Wiley
Date: 04-2007
Alteration of Adenosine Receptors in Patients with Chronic Obstructive Pulmonary Disease
Publisher: American Thoracic Society
Date: 15-02-2006
AIRWAYS-ICPs (European Innovation Partnership on Active and Healthy Ageing) from concept to implementation
Publisher: European Respiratory Society (ERS)
Date: 04-2016
Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease
Publisher: Elsevier BV
Date: 2016
The ERS Research Agency: the beginning
Publisher: European Respiratory Society (ERS)
Date: 04-2016
DOI: 10.1183/13993003.02109-2015
Abstract: There is at the current time a significant opportunity for the ERS to leverage its experience and reputation as an international umbrella organisation to promote high-quality, multinational respiratory research with the goal of improving the health of respiratory patients. This editorial proposes a model for the role and structure of an ERS Research Agency. It is based upon research, implicit knowledge and explicit feedback from ERS members and selected external in iduals and organisations.As with any new endeavour there are challenges and threats. Building a Research Agency will be a major undertaking that will require significant organisational planning, resources, effort and commitment.Organisations with multiple stakeholders tend to have a status quo inertia that has to be overcome for any significant new endeavour. The ERS Research Agency could be an investment in the future of respiratory research.
New Insights on the Possible Role of Mast Cells in Aspirin-Induced Asthma
Publisher: Bentham Science Publishers Ltd.
Date: 06-2009
DOI: 10.2174/1874467210902020182
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are major drugs used in the treatment of inflammation and pain in a wide variety of disorders. The best-known mechanism of action of NSAIDs is the inhibition of prostaglandin synthesis as a result of their action on cyclooxygenase (COX) enzymes. However, data have been accumulating through the years indicating that NSAIDs also act on other targets in cell signaling. It has been established that NSAIDs induce anti-inflammatory effects independent of COX. Acetylsalicylic acid (ASA) and other inhibitors of COX induce severe bronchospasms and asthmatic attacks in a significant population of asthmatic patients. The etiology of ASA induced asthma is complex and not fully understood, but most evidence points towards an abnormality of arachidonic acid (AA) metabolism. Since doses of ASA necessary to treat chronic inflammatory diseases appeared much higher than those required to inhibit PG synthesis, COX-independent mechanisms of NSAIDs were postulated. Recently, we have shown that NSAIDs induced expression of heat shock proteins specially HSP70. Heat shock proteins (HSPs) are normal intracellular proteins that are produced in greater amounts when cells are subjected to stress or injury. Interestingly, a potential pathogenic role for heat shock proteins in diseases such as autoimmune disease, vascular disease has been reported. Because mast cells have been reported to play a role in the pathogenesis of ASA induced asthma, a link between heat shock proteins and this disease could postulated. In this review, an overview is given on aspirin-induced asthma and the cells and mediators that may play a role therein. Mast cell signaling with regard to interaction with NSAIDs and heat shock proteins (HSPs) and toll-like receptors (TLRs) is further highlighted.
Importin‐7 mediates glucocorticoid receptor nuclear import and is impaired by oxidative stress, leading to glucocorticoid insensitivity
Publisher: Wiley
Date: 09-08-2013
DOI: 10.1096/FJ.12-222604
Abstract: Some patients with severe inflammatory disease fail to respond to glucocorticoids, and oxidative stress contributes to this insensitivity. Importin receptors are associated with nuclear translocation of the glucocorticoid receptor (GR), which is essential for glucocorticoid function. We hypothesized that importin-7 is central to GR nuclear translocation and glucocorticoid sensitivity. We investigated the effects of importin-7 siRNA on fluticasone propionate (FP)-induced GR nuclear localization and suppression of IL-1β-induced CXCL8 and the effects of hydrogen peroxide (H2O2) plus IL-1β costimulation on importin-7 expression, function, and glucocorticoid responsiveness in a human macrophagecell line (U937). H2O2 significantly reduced FP-induced GR nuclear localization (3.4±0.51- vs. 5.7±0.85-fold increase, P<0.05) and suppression of IL-1β-induced CXCL8 (62.3±2.3 vs. 85.1±7.0%, P<0.05). Knockdown of importin-7 by 38.4 ± 11.5% (compared with control siRNA) significantly reduced FP-mediated GR nuclear localization (3.5±0.5- vs. 5.7±0.85-fold increase, P<0.05) and suppression of IL-1β-induced CXCL8 expression (40.2±16.1 vs. 68.4±3.0%, P<0.05). H2O2 plus IL-1β had no direct effect on importin-7 but caused a significant loss (61.2±12.6% compared with baseline) of nuclear RanGTP, an essential cofactor for importin-7-mediated nuclear import of cargo proteins. The importin-7 complex is essential for glucocorticoid function, and the expression of its cofactor RanGTP is reduced during oxidative stress-induced glucocorticoid insensitivity.
Neutrophilic inflammation in sputum does not define a clinical distinct asthma phenotype in ATLANTIS
Publisher: European Respiratory Society
Date: 05-09-2021
Steroid resistance in asthma
Publisher: Oxford University Press (OUP)
Date: 07-1995
SNP Rs11614913 in miR-196a is a risk factor for non-small cell lung cancer in Iranians
Publisher: European Respiratory Society
Date: 07-09-2020
Role of Stem Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Pulmonary Emphysema
Publisher: Informa UK Limited
Date: 03-09-2018
DOI: 10.1080/15412555.2018.1536116
Abstract: There are only few human translational studies performed in the area of stem cell research in patients with chronic obstructive pulmonary disease (COPD) and/or pulmonary emphysema. Before progress to clinical trials with stem cells we strongly believe that more human translational studies are essential, otherwise, the clinical rationale would be solely based on limited in vitro and animal studies. In the future, stem cell therapy could be a treatment for this incurable disease. As of now, stem cell therapy is still to be considered as an area of active research, lacking any strong rationale for performing clinical trials in COPD. Although stem cells would be likely to represent a heterogeneous population of cells, the different cell subsets and their importance in the pathogenesis of the different clinical phenotypes need to be fully characterised before progressing to clinical trials. Moreover, the potential side effects of stem cell therapy are underestimated. We should not ignore that some of the most deadly neoplasms are arising from stem cells.
Epithelial–stromal cell interactions and extracellular matrix mechanics drive the formation of airway-mimetic tubular morphology in lung organoids
Publisher: Elsevier BV
Date: 09-2021
Low-dose Theophylline Reduces Eosinophilic Inflammation but Not Exhaled Nitric Oxide in Mild Asthma
Publisher: American Thoracic Society
Date: 15-07-2001
DOI: 10.1164/AJRCCM.164.2.2006043
Abstract: Theophylline is well-established in the management of asthma, and there is some evidence of an antiinflammatory effect in asthma. It is not known whether theophylline affects inflammatory markers such as sputum eosinophils and exhaled nitric oxide (NO) in patients with mild asthma not receiving inhaled steroid therapy. In a double-blind, placebo-controlled, cross-over study of 15 patients with mild asthma, we assessed the effect of low-dose theophylline therapy (250 mg twice per day) on eosinophils in induced sputum, bronchoalveolar lavage (BAL) and airway biopsies at the end of both the treatment and placebo periods. Measurements of exhaled nitric oxide (NO) were made at the end of the active and placebo treatment periods of 5 wk each. Low-dose theophylline (mean serum level, 6.1 mg/L) led to a significant reduction in mean (95% confidence interval [CI]) sputum eosinophils from 11.3% (7.80-14.76%) to 8.0% (5.46-10.44%), BAL eosinophils from 3.4% (2.4-4.4%) to 1.7% (1.1-2.3%) and biopsy eosinophils from 1.83% (0.76-2.89%) to 1.20% (0.27-2.13%) compared with placebo (all p < 0.05). There was no significant change in levels of exhaled NO or improvement in lung function and bronchial responsiveness. Low-dose theophylline induced antiinflammatory effects in asthma, reflected by a fall in airway eosinophils with no change in exhaled NO or changes in lung function.
Chemokines and Chemokine Receptors Blockers as New Drugs for the Treatment of Chronic Obstructive Pulmonary Disease
Publisher: Bentham Science Publishers Ltd.
Date: 31-10-2013
DOI: 10.2174/09298673113206660261
Abstract: Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response of the lung to noxious particles or gases. The cellular inflammatory response in COPD is characterised by an increased number of inflammatory cells in the lungs. Although the molecular and cellular mechanisms responsible for the development of COPD are not well understood several mediators are assumed to regulate the activation and recruitment of these inflammatory cells into the lung of COPD patients particularly those belonging to the chemokine family. Inhibitors or blockers of chemokine and chemokine receptors are therefore of great interest as potential novel therapies for COPD and many are now in clinical development. A high degree of redundancy exists in the chemokine network and inhibition of a single chemokine or receptor may not be sufficient to block the inflammatory response. Despite this, animal studies suggest a strong rationale for inhibiting the chemokine network in COPD. As such, every leading pharmaceutical company maintains a significant interest in developing agents that regulate leukocyte navigation as potential anti-inflammatory drugs. Drugs and antibodies targeting chemokines and their receptors are generally still in early stages of development and the results of clinical trial are awaited with great interest. These agents may not only provide improved management of COPD but also, importantly, indicate proof-of-concept to further clarify the role of chemokines in the pathophysiology of COPD.
Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study
Publisher: European Respiratory Society (ERS)
Date: 05-02-2009
DOI: 10.1183/09031936.00158208
Abstract: Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.
Decreased neutrophil‐mediated bacterial killing in COVID‐19 patients
Publisher: Wiley
Date: 11-06-2021
DOI: 10.1111/SJI.13083
Abstract: The coronavirus disease COVID‐19 was first described in December 2019. The peripheral blood of COVID‐19 patients have increased numbers of neutrophils which are important in controlling the bacterial infections observed in COVID‐19. We sought to evaluate the cytotoxic capacity of neutrophils in COVID‐19 patients. 34 confirmed COVID‐19 patients (29 severe, five mild disease), and nine healthy controls were recruited from the Masih Daneshvari Hospital (Tehran, Iran) from March to May 2020. Polymorphonuclear (PMN) cells were isolated from whole blood and incubated with green fluorescent protein (GFP)‐labelled methicillin‐resistant Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) . Bacterial growth was determined by measuring the florescence of co‐cultures of bacteria and neutrophils and reported as the lag time before exponential growth. The number of viable bacteria was determined after 70 hours as colony‐forming units (CFU). The immunophenotype of tested cells was evaluated by flow cytometry. Isolated neutrophils have higher surface expression of CD16 and CD62L with negative markers for PMN‐MDSC. Bacterial growth in the presence of SA (22 ± 0.9 versus 9.2 ± 0.5 h, P .01) and PA (12.4 ± 0.6 versus 4.5 ± 0.22, P .01) was significantly reduced in COVID‐19 patients. After 70 h incubation of PMN with bacteria (SA and PA), CFUs were significant increased in COVID‐19 patients SA (2.6 ± 0.09 × 10 8 CFU/mL‐severe patients and 1.4 ± 0.06 × 10 8 CFU/mL‐mild patients, P .001) and PA (2.2 ± 0.09 × 10 9 CFU/mL‐severe patients and 1.6 ± 0.03 × 10 9 CFU/mL‐mild patients, P .001). Gentamycin proliferation assays confirmed the presence of intracellular bacteria. Reduced bacterial killing by neutrophils from COVID‐19 patients may be responsible for the high bacterial yield seen in these patients.
Overcoming Reduced Glucocorticoid Sensitivity in Airway Disease
Publisher: Springer Science and Business Media LLC
Date: 05-2010
DOI: 10.2165/10898520-000000000-00000
Abstract: There is a considerable and growing unmet medical need in respiratory disease concerning effective anti-inflammatory therapies for conditions such as severe asthma, chronic obstructive pulmonary disease and cystic fibrosis. These diseases share a predominant characteristic of an enhanced and uncontrolled inflammatory response in the lungs, which contributes to disease progression, hospitalization and mortality. These diseases are poorly controlled by current anti-inflammatory therapies including glucocorticoids, which are otherwise effective in many other inflammatory conditions or in milder disease such as asthma. The exact cause of this apparent impairment of glucocorticoid function remains largely unclear however, recent studies have now implicated a number of possible mechanisms. Central among these is an elevation of the oxidant burden in the lungs and the resulting reduction in the activity of histone deacetylase (HDAC)-2. This contributes to both the enhancement of proinflammatory mediator expression and the impaired ability of the glucocorticoid receptor (GR)-alpha to repress proinflammatory gene expression. The oxidant-mediated reduction in HDAC-2 activity is, in part, a result of an elevation in the phosphoinositol 3-kinase (PI3K) delta/Akt signalling pathway. Blockade of the PI3Kdelta pathway restores glucocortiocoid function in both in vitro and in vivo models, and in primary cells from disease. In addition, inhibition of the PI3Kdelta and PI3Kgamma isoforms is anti-inflammatory in both innate and adaptive immune responses. Consequently, selective inhibition of this pathway may provide a therapeutic strategy both as a novel anti-inflammatory and in combination therapy with glucocorticoids to restore their function. However, a number of other oxidant-related and -unrelated mechanisms, including altered kinase signalling and expression of the dominant negative GRbeta, may also play a role in the development of glucocorticoid insensitivity. Further elucidation of these mechanisms and pathways will enable novel therapeutic targeting for alternative anti-inflammatory drugs or combination therapies providing restoration for the anti-inflammatory action of glucocorticoids.
Translational Analysis of Moderate to Severe Asthma GWAS Signals Into Candidate Causal Genes and Their Functional, Tissue-Dependent and Disease-Related Associations
Publisher: Frontiers Media SA
Date: 18-10-2021
DOI: 10.3389/FALGY.2021.738741
Abstract: Asthma affects more than 300 million people globally and is both under diagnosed and under treated. The most recent and largest genome-wide association study investigating moderate to severe asthma to date was carried out in 2019 and identified 25 independent signals. However, as new and in-depth downstream databases become available, the translational analysis of these signals into target genes and pathways is timely. In this study, unique (U-BIOPRED) and publicly available datasets (HaploReg, Open Target Genetics and GTEx) were investigated for the 25 GWAS signals to identify 37 candidate causal genes. Additional traits associated with these signals were identified through PheWAS using the UK Biobank resource, with asthma and eosinophilic traits amongst the strongest associated. Gene expression omnibus dataset examination identified 13 candidate genes with altered expression profiles in the airways and blood of asthmatic subjects, including MUC5AC and STAT6 . Gene expression analysis through publicly available datasets highlighted lung tissue cell specific expression, with both MUC5AC and SLC22A4 genes showing enriched expression in ciliated cells. Gene enrichment pathway and interaction analysis highlighted the dominance of the HLA-DQA1/A2/B1/B2 gene cluster across many immunological diseases including asthma, type I diabetes, and rheumatoid arthritis. Interaction and prediction analyses found IL33 and IL18R1 to be key co-localization partners for other genes, predicted that CD274 forms co-expression relationships with 13 other genes, including the HLA-DQA1/A2/B1/B2 gene cluster and that MUC5AC and IL37 are co-expressed. Drug interaction analysis revealed that 11 of the candidate genes have an interaction with available therapeutics. This study provides significant insight into these GWAS signals in the context of cell expression, function, and disease relationship with the view of informing future research and drug development efforts for moderate-severe asthma.
Dexamethasone inhibits ozone‐induced gene expression of macrophage inflammatory protein‐2 in rat lung
Publisher: Wiley
Date: 24-04-1995
DOI: 10.1016/0014-5793(95)00333-5
Abstract: To address the potential role of the chemokine macrophage inflammatory protein-2 (MIP-2) in airway inflammation, we examined whether MIP-2 may play a role in ozone-induced neutrophilic inflammation of airways and its modulation by dexamethasone in rat lung. Following ozone exposure, MIP-2 mRNA expression in the lung peaked at 2 h after exposure and slowly declined thereafter. Dexamethasone suppressed ozone-induced MIP-2 mRNA expression and neutrophil accumulation in the lung. We suggest that the MIP-2 mRNA induction may switch on the neutrophilic influx observed in this model of lung inflammation. Furthermore, the MIP-2 expression is regulated by dexamethasone which may represent one of the mechanisms by which glucocorticoids exert their potent anti-inflammatory properties.
Models of respiratory disease symposium
Publisher: Springer Science and Business Media LLC
Date: 08-2013
Dealing with Stress: Defective Metabolic Adaptation in Chronic Obstructive Pulmonary Disease Pathogenesis
Publisher: American Thoracic Society
Date: 11-2017
Effects of Toll Like Receptor Agonists and SARS-Cov-2 Antigens on Interferon (IFN) Expression by Peripheral Blood CD3+ T Cells in COVID-19 Patients
Publisher: MDPI AG
Date: 30-12-2022
DOI: 10.20944/PREPRINTS202212.0577.V1
Abstract: Background: Signaling by toll like receptors (TLRs) initiates important immune responses against viral infection. The role of TLRs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is not well elucidated. Thus, we investigated the interaction of TLRs agonists and SARS-COV-2 antigens with immune cells in vitro. Material & methods: 30 coronavirus disease 2019 (COVID-19) patients (15 severe and 15 moderate) and 10 age and sex matched control (HC) were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and activated with TLR3, 7, 8 and 9 agonists, the spike protein (SP) of SARS-CoV-2 and the Receptor Binding Domain (RBD) unit of SP. Frequencies of CD3+IFN-& beta + T cells, and CD3+IFN-g+ T cells was evaluated by flow cytometry. Interferon (IFN)-b gene expression was assessed by qRT-PCR. Results: The frequency of CD3+IFN-& beta + T cells was higher in moderate and severe patients at baseline in comparison with HCs. Stimulation of PBMCs from moderate patients with SP and TLR8 agonist significantly upregulated the frequency of CD3+IFN-& beta + T cells (P=0.0005 and 0.0024, respectively) when compared to non-stimulated (NS) s les. The greatest increase in CD3+IFN-b+ T cell frequency in PBMCs from severe patients was seen with TLR8 and TLR7 agonists when compared to NS (P= 0.003 and 0.0167, respectively). TLR stimulation did not significantly enhance the frequency of CD3+IFN-g+ T cells generated from PBMCs from moderate and severe patients compared with unstimulated controls. However, the frequency of CD3+IFN-ɣ+ T cells in PBMCs from moderate patients was upregulated by agonists of TLR3, 8 and 9, SP and RBD when compared with NS s les from HCs. The expression of the IFN-& beta gene after stimulation of CD3+T cells with the TLR8 agonist was also up-regulated in moderate than severe patients (moderate vs. severe: p=0.0006). In addition, stimulation of CD3+ T cells with SP, up-regulated the expression of IFN-& beta gene expression in cells from patients with moderate disease (moderate vs. severe: p=0.01). Conclusion: Stimulation of PBMCs from COVID-19 patients with a TLR8 agonist and with SP enhanced IFN-b protein and gene levels. This may potentiate immune responses against SARS-CoV-2 infection and prevent viral replication and spread.
International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma
Publisher: European Respiratory Society (ERS)
Date: 12-12-2013
DOI: 10.1183/09031936.00202013
Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
Airways diseases: insights from the European Respiratory Society Annual Congress 2017
Publisher: AME Publishing Company
Date: 11-2017
Effects of hydrogen sulfide on ozone-induced features of chronic obstructive pulmonary disease
Publisher: European Respiratory Society
Date: 09-2015
New drugs targeting Th2 lymphocytes in asthma
Publisher: Springer Science and Business Media LLC
Date: 2008
Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation
Publisher: Frontiers Media SA
Date: 07-07-2023
DOI: 10.3389/FIMMU.2023.1192028
Abstract: The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss. RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3’-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets’ steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression. Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells.
Addressing unmet needs in understanding asthma mechanisms
Publisher: European Respiratory Society (ERS)
Date: 05-2017
DOI: 10.1183/13993003.02448-2016
Abstract: Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.
Determinants of expression of SARS‐CoV‐2 entry‐related genes in upper and lower airways
Publisher: Wiley
Date: 03-11-2021
DOI: 10.1111/ALL.15152
Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.JACI.2005.06.034
Abstract: Reactive nitrogen species, formed via the reaction of nitric oxide (NO) with superoxide anion and via (myelo)peroxidase-dependent oxidation of NO(2)(-), have potent proinflammatory and oxidizing actions. Reactive nitrogen species formation and nitrosative stress are potentially involved in chronic obstructive pulmonary disease (COPD) pathogenesis. To investigate the expression of markers of nitrosative stress, including nitrotyrosine (NT), inducible NO synthase (iNOS), endothelial NO synthase (eNOS), myeloperoxidase (MPO), and xanthine oxidase (XO) in bronchial biopsies and bronchoalveolar lavage from patients with mild to severe stable COPD compared with control groups (smokers with normal lung function and nonsmokers). The expression of NT, iNOS, eNOS, MPO and XO in the bronchial mucosa and bronchoalveolar lavage of patients was measured by using immunohistochemistry, Western blotting, and ELISA and correlated with the inflammatory cell profile. Patients with severe COPD in stable phase had higher numbers of NT(+) and MPO(+) cells in their bronchial submucosa compared with mild/moderate COPD, smokers with normal lung function, and nonsmokers (P < .01). iNOS(+) and eNOS(+) but not XO(+) cells were significantly increased in smokers with COPD or normal lung function compared with nonsmokers (P < .05 and P < .01, respectively). In patients with COPD, the number of MPO(+) cells was significantly correlated with the number of neutrophils (r = +0.61 P < .0025) in the bronchial submucosa. Furthermore, the number of NT(+) and MPO(+) cells was negatively correlated with postbronchodilator FEV(1). These data suggest that nitrosative stress, mainly mediated by MPO and neutrophilic inflammation, may contribute to the pathogenesis of severe COPD.
Steroid Resistance in Severe Asthma: Current Mechanisms and Future Treatment
Publisher: Bentham Science Publishers Ltd.
Date: 03-2011
DOI: 10.2174/138161211795428984
Abstract: The disproportionate cost of treating asthmatic patients who do not respond to conventional anti-inflammatory therapies makes delineation of the mechanism for glucocorticoid resistance an important field of asthma research. Unbiased cluster analysis indicates that asthma is a syndrome with a number of distinct phenotypes and 5-10% of asthmatics fall into this category of relative glucocorticoid insensitivity. This sub-population is itself ided into smaller subsets which have different underlying mechanisms for this relative glucocorticoid resistance ranging from an inherited genetic basis to specific kinase signalling pathways triggered by exposure to environmental stressors such as cigarette smoking or infection. Whilst the underlying mechanisms are becoming better understood there remains a lack of effective novel therapies. However it is clear that relative glucocorticoid insensitive patients who are smokers should be encouraged to quit, thereby reducing their oxidant load. Novel treatments will consist of either developing new anti-inflammatory treatments targeting pathways aberrantly activated in these patients or of suppressing signalling pathways that attenuate glucocorticoid receptor function and thereby restoring glucocorticoid sensitivity. It will be important to uncover non-invasive biomarkers for aberrant pathway activation and for discerning which components of glucocorticoid receptor activation are abnormal if future treatments are to be tailored to address these specific issues. Conventional combination therapies will continue to be used in the near future but additional add-on treatments using drugs directed against aberrantly expressed inflammatory pathways or mediators along with an inhaled glucocorticoid are likely to prove the most effective new therapies in the future.
Recent evidence from omic analysis for redox signalling and mitochondrial oxidative stress in COPD
Publisher: Springer Science and Business Media LLC
Date: 11-07-2022
DOI: 10.1186/S12950-022-00308-9
Abstract: COPD is driven by exogenous and endogenous oxidative stress derived from inhaled cigarette smoke, air pollution and reactive oxygen species from dysregulated mitochondria in activated inflammatory cells within the airway and lung. This is compounded by the loss in antioxidant defences including FOXO and NRF2 and other antioxidant transcription factors together with various key enzymes that attenuate oxidant effects. Oxidative stress enhances inflammation airway remodelling including fibrosis and emphysema post-translational protein modifications leading to autoantibody generation DNA damage and cellular senescence. Recent studies using various omics technologies in the airways, lungs and blood of COPD patients has emphasised the importance of oxidative stress, particularly that derived from dysfunctional mitochondria in COPD and its role in immunity, inflammation, mucosal barrier function and infection. Therapeutic interventions targeting oxidative stress should overcome the deleterious pathologic effects of COPD if targeted to the lung. We require novel, more efficacious antioxidant COPD treatments among which mitochondria-targeted antioxidants and Nrf2 activators are promising.
S119 Mapping mouse models of severe asthma onto human disease
Publisher: BMJ Publishing Group Ltd and British Thoracic Society
Date: 15-11-2017
Induction and regulation of matrix metalloproteinase-12in human airway smooth muscle cells
Publisher: Springer Science and Business Media LLC
Date: 12-2005
Abstract: The elastolytic enzyme matrix metalloproteinase (MMP)-12 has been implicated in the development of airway inflammation and remodeling. We investigated whether human airway smooth muscle cells could express and secrete MMP-12, thereby participating in the pathogenesis of airway inflammatory diseases. Laser capture microdissection was used to collect smooth muscle cells from human bronchial biopsy sections. MMP-12 mRNA expression was analysed by quantitative real-time RT-PCR. MMP-12 protein expression and secretion from cultured primary airway smooth muscle cells was further analysed by Western blot. MMP-12 protein localization in bronchial tissue sections was detected by immunohistochemistry. MMP-12 activity was determined by zymography. The TransAM AP-1 family kit was used to measure c-Jun activation and nuclear binding. Analysis of variance was used to determine statistical significance. We provide evidence that MMP-12 mRNA and protein are expressed by in-situ human airway smooth muscle cells obtained from bronchial biopsies of normal volunteers, and of patients with asthma, COPD and chronic cough. The pro-inflammatory cytokine, interleukin (IL)-1β, induced a -fold increase in MMP-12 gene expression and a -fold enhancement in MMP-12 activity of primary airway smooth muscle cell cultures. Selective inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase and phosphatidylinositol 3-kinase reduced the activity of IL-1β on MMP-12, indicating a role for these kinases in IL-1β-induced induction and release of MMP-12. IL-1β-induced MMP-12 activity and gene expression was down-regulated by the corticosteroid dexamethasone but up-regulated by the inflammatory cytokine tumour necrosis factor (TNF)-α through enhancing activator protein-1 activation by IL-1β. Transforming growth factor-β had no significant effect on MMP-12 induction. Our findings indicate that human airway smooth muscle cells express and secrete MMP-12 that is up-regulated by IL-1β and TNF-α. Bronchial smooth muscle cells may be an important source of elastolytic activity, thereby participating in remodeling in airway diseases such as COPD and chronic asthma.
Elevated CXCL-8 expression in bronchoalveolar lavage correlates with disease severity in patients with acute respiratory distress syndrome resulting from tuberculosis
Publisher: Springer Science and Business Media LLC
Date: 05-08-2014
MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients
Publisher: Wiley
Date: 28-08-2009
DOI: 10.1111/J.1365-2559.2009.03377.X
Abstract: Mucus expectoration is a common feature of chronic obstructive pulmonary disease (COPD). MUC5AC and MUC5B, the major mucins, are released predominantly from submucosal glands in the central airways. The aim was to investigate gland size and MUC5AC and MUC5B expression in bronchial rings from smokers with COPD compared with control groups. Bronchial rings from 10 non-smoking subjects, 20 smokers with normal lung function and 20 smokers with COPD were studied. Periodic acid-Schiff (PAS) and Alcian blue histochemistry and MUC5AC and MUC5B immunohistochemistry followed by quantification of the immunoreactive area was performed. The area occupied by MUC5AC+ cells in bronchial submucosal glands was increased in COPD [20% (5.5-31.7%) gland area] compared with smokers with normal lung function [9.5% (2.5-17.5%) P < 0.05] and non-smoking subjects [2% (0.4-6.2%) P < 0.05]. The area occupied by MUC5AC+ cells in the bronchial surface epithelium was also increased in smokers (with/without COPD) [73.5% (25-92%) epithelial area] compared with non-smoking subjects [15% (2.7-32%) P < 0.01]. Gland size, PAS, Alcian blue staining and MUC5B expression were not significantly different among groups. MUC5AC expression correlated with the degree of airflow obstruction. MUC5AC and MUC5B expression correlated with pack-years. COPD is associated with increased MUC5AC expression in submucosal glands, indicating that MUC5AC may be involved in the pathophysiology of the disease.
Decreased percentage of CD4+Foxp3+TGF-β+ and increased percentage of CD4+IL-17+ cells in bronchoalveolar lavage of asthmatics
Publisher: Springer Science and Business Media LLC
Date: 09-08-2014
Correction: Cigarette Smoke Induced Airway Inflammation Is Independent of NF-κB Signalling
Publisher: Public Library of Science (PLoS)
Date: 16-10-2013
DOI: 10.1371/ANNOTATION/754D7B19-2DAC-479B-A23C-DB9FED0431BE
Medication Adherence in Patients With Severe Asthma Prescribed Oral Corticosteroids in the U-BIOPRED Cohort
Publisher: Elsevier BV
Date: 07-2021
Inhibition of PI3Kδ Restores Glucocorticoid Function in Smoking-induced Airway Inflammation in Mice
Publisher: American Thoracic Society
Date: 04-2009
Molecular Mechanisms of Corticosteroid Resistance
Publisher: Elsevier BV
Date: 08-2008
Abstract: Most patients with asthma are successfully treated with conventional therapy. Nevertheless, there is a small proportion of asthmatic patients, including present cigarette smokers and former cigarette smokers, who fail to respond well to therapy with high-dose glucocorticoids (GCs) or with supplementary therapy. In addition, high doses of steroids have a minimal effect on the inexorable decline in lung function in COPD patients and only a small effect on reducing exacerbations. GC insensitivity, therefore, presents a profound management problem in these patients. GCs act by binding to a cytosolic GC receptor (GR), which is subsequently activated and is able to translocate to the nucleus. Once in the nucleus, the GR either binds to DNA and switches on the expression of antiinflammatory genes or acts indirectly to repress the activity of a number of distinct signaling pathways such as nuclear factor (NF)-kappaB and activator protein (AP)-1. This latter step requires the recruitment of corepressor molecules. Importantly, this latter interaction is mutually repressive in that high levels of NF-kappaB and AP-1 attenuate GR function. A failure to respond may therefore result from reduced GC binding to GR, reduced GR expression, enhanced activation of inflammatory pathways, or lack of corepressor activity. These events can be modulated by oxidative stress, T-helper type 2 cytokines, or high levels of inflammatory mediators, all of which may lead to a reduced clinical outcome. Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new antiinflammatory drugs or may reverse the relative steroid insensitivity that is characteristic of patients with these diseases.
Enrichment of the Janus kinase (JAK) activation signature in severe asthma sputum: Correlation with IL-13 expression
Publisher: European Respiratory Society
Date: 09-2016
Relationship between mitochondrial function and cellular ageing depends upon compartment analysed
Publisher: European Respiratory Society
Date: 09-2016
Interaction between type 2 cytokine and inflammasome responses in the pathogenesis of obesity-associated asthma
Publisher: European Respiratory Society
Date: 04-09-2022
Regulation of Th2 Cytokine Genes by p38 MAPK-Mediated Phosphorylation of GATA-3
Publisher: The American Association of Immunologists
Date: 15-02-2007
DOI: 10.4049/JIMMUNOL.178.4.2491
Abstract: GATA-3 plays a critical role in allergic diseases by regulating the release of cytokines from Th2 lymphocytes. However, the molecular mechanisms involved in the regulation of GATA-3 in human T lymphocytes are not yet understood. Using small interfering RNA to knock down GATA-3, we have demonstrated its critical role in regulating IL-4, IL-5, and IL-13 release from a human T cell line. Specific stimulation of T lymphocytes by costimulation of CD3 and CD28 to mimic activation by APCs induces translocation of GATA-3 from the cytoplasm to the nucleus, with binding to the promoter region of Th2 cytokine genes, as determined by chromatin immunoprecipitation. GATA-3 nuclear translocation is dependent on its phosphorylation on serine residues by p38 MAPK, which facilitates interaction with the nuclear transporter protein importin-α. This provides a means whereby allergen exposure leads to the expression of Th2 cytokines, and this novel mechanism may provide new approaches to treating allergic diseases.
Update on glucocorticoid action and resistance
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.JACI.2006.01.032
Abstract: Extensive development of inhaled and oral glucocorticoids has resulted in highly potent molecules that have been optimized to target activity to the lung and minimize systemic exposure. These have proved highly effective for most asthmatic subjects, but despite these developments, there are a number of subjects with asthma who fail to respond to even high doses of inhaled or even oral glucocorticoids. Advances in delineating the fundamental mechanisms of glucocorticoid pharmacology, especially the concepts of transactivation and transrepression and cofactor recruitment, have resulted in better understanding of the molecular mechanisms whereby glucocorticoids suppress inflammation. The existence of multiple mechanisms underlying glucocorticoid insensitivity raises the possibility that this might indeed reflect different diseases with a common phenotype, and studies examining the efficacy of potential new agents should be targeted toward subgroups of patients with severe corticosteroid-resistant asthma who clearly require effective new drugs and other approaches to improved asthma control.
5-Azacytidine suppresses RNA polymerase II recruitment to the SLPI gene
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.BBRC.2005.03.138
Abstract: Histone methylation is regarded as a stable modification important in the epigenetic regulation of gene expression. Transcriptionally active chromatin is methylated at H3-K4 whereas repressed chromatin is methylated at H3-K9. To investigate the role of histone methylation in an acute inflammatory response, A549 cells were treated with IL-1beta and/or the methylase inhibitor 5-azacytidine (5-aza), and histone H3-K4 methylation levels and transcription of secretory leukocyte protease inhibitor (SLPI) were measured. IL-1beta stimulation enhanced histone H3-K4 tri-methylation across the SLPI coding region at 24h. In parallel, IL-1beta enhanced recruitment of RNA polymerase II to the SLPI gene. 5-aza attenuated both H3-K4 tri-methylation and RNA polymerase II recruitment to a similar extent resulting in reduced SLPI mRNA and protein levels. These data suggest that in addition to epigenetic regulation of constitutive SLPI expression, H3-K4 tri-methylation may play a role in stimulated SLPI expression by modulating RNA polymerase II recruitment and subsequent gene transcription.
IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and disease status
Publisher: Cold Spring Harbor Laboratory
Date: 21-10-2022
DOI: 10.1101/2022.10.20.513024
Abstract: IL-33 can activate Th2 cells after binding to the IL-1RL1/IL-1RAcP receptor. However, it is unknown whether disease or genetic make-up regulate IL33 responsiveness of Th2 cells. We investigated whether IL-1RL1 asthma risk haplotypes or asthma status influence IL-33-induced Th2 transcriptomic responses in vitro . CD4 + T cells from 16 asthma patients and matched controls, stratified for IL-1RL1 haplotype, were differentiated into Th2 effector cells, and re-stimulated in the presence or absence of IL-33, followed by RNA-sequencing and differential gene expression analysis. Association of IL-33-induced gene signatures with clinical parameters was tested in U-BIOPRED sputum transcriptomic data. Presence of IL-33 during Th2 cell re-stimulation results in extensive changes in gene expression, affecting a large proportion of the activated Th2 cell transcriptome. IL-33 induced more genes in Th2 cells from donors with asthma than in controls. However, the IL-33 effects were strongest in Th2 cells carrying the IL-1RL1 risk haplotype, as evidenced by a significantly increased effect size compared to controls. A gene signature of IL-33 induced genes in Th2 cells showed a strong positive correlation with macrophage counts and pauci-granulocytic asthma in sputum transcriptomic data from the U-BIOPRED study. The risk IL-1RL1 haplotype strongly increases the sensitivity of Th2 effector cell for IL-33-mediated regulation of gene expression, while asthma status has an independent effect. The IL-33 gene signature was not associated with type-2 high or eosinophilic asthma in sputum transcriptomic data from U-BIOPRED. Cellular sensitivity to IL-33 depends on genetic makeup and asthma disease status. IL-33 strongly alters gene expression of activated Th2 cells, dependent on asthma disease status and IL-1RL1 risk haplotype. IL-33 driven gene signature in sputum transcriptomic data identifies pauci-granulocytic asthma.
COPD immunopathology
Publisher: Springer Science and Business Media LLC
Date: 13-05-2016
An unusual case of congenital short trachea with very long bronchi mimicking bronchial asthma
Publisher: BMJ
Date: 04-2002
Abstract: Case reports of a short trachea with early branching of the main bronchi are uncommon. The case is presented of a 64 year old woman with upper airway obstruction due to this anatomical abnormality which caused breathlessness and wheezing that was misdiagnosed (and treated) as bronchial asthma for many years.
Nutritional Impact and Its Potential Consequences on COVID-19 Severity
Publisher: Frontiers Media SA
Date: 05-07-2021
Abstract: Background: During late 2019 a viral disease due to a novel coronavirus was reported in Wuhan, China, which rapidly developed into an exploding pandemic and poses a severe threat to human health all over the world. Until now (May 2021), there are insufficient treatment options for the management of this global disease and shortage of vaccines. Important aspects that help to defeat coronavirus infection seems to be having a healthy, strong, and resilient immune system. Nutrition and metabolic disorders, such as obesity and diabetes play a crucial role on the community health situation in general and especially during this new pandemic. There seems to be an enormous impact of lifestyle, metabolic disorders, and immune status on coronavirus disease 2019 (COVID-19) severity and recovery. For this reason, it is important to consider the impact of lifestyle and the consumption of well-defined healthy diets during the pandemic. Aims: In this review, we summarise recent findings on the effect of nutrition on COVID-19 susceptibility and disease severity and treatment. Understanding how specific dietary features might help to improve the public health strategies to reduce the rate and severity of COVID-19.
Mecanismos moleculares de los glucocorticoides
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1157/13070282
Triamcinolone Acetonide and Dexamethasome Suppress TNF‐α‐Induced Histone H4 Acetylation on Lysine Residues 8 and 12 in Mononuclear Cells
Publisher: Wiley
Date: 11-2002
Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation ( PVT1 ) as a novel regulator of the asthmatic phenotype in human airway smooth muscle
Publisher: Elsevier BV
Date: 03-2017
The Detrimental Health Effects of Traffic-related Air Pollution
Publisher: American Thoracic Society
Date: 04-2009
LIGAND-INDUCED DIFFERENTIATION OF GLUCOCORTICOID RECEPTOR (GR) TRANS-REPRESSION AND TRANSACTIVATION
Publisher: Portland Press Ltd.
Date: 05-1996
DOI: 10.1042/BST024267S
Oxidative stress and inflammation: The link between COPD and lung cancer
Publisher: Elsevier BV
Date: 06-2012
How can we minimise the use of regular oral corticosteroids in asthma?
Publisher: European Respiratory Society (ERS)
Date: 05-02-2020
DOI: 10.1183/16000617.0085-2019
Abstract: Options to achieve oral corticosteroid (OCS)-sparing have been triggering increasing interest since the 1970s because of the side-effects of OCSs, and this has now become achievable with biologics. The Société de Pneumologie de Langue Française workshop on OCSs aimed to conduct a comprehensive review of the basics for OCS use in asthma and issue key research questions. Pharmacology and definition of regular use were reviewed by the first working group (WG1). WG2 examined whether regular OCS use is associated with T2 endotype. WG3 reported on the specificities of the paediatric area. Key “research statement proposals” were suggested by WG4. It was found that the benefits of regular OCS use in asthma outside episodes of exacerbations are poorly supported by the existing evidence. However, complete OCS elimination couldn’t be achieved in any available studies for all patients and the panel felt that it was too early to conclude that regular OCS use could be declared criminal. Repeated or prolonged need for OCS beyond 1 g·year −1 should indicate the need for referral to secondary/tertiary care. A strategic sequential plan aiming at reducing overall exposure to OCS in severe asthma was then held as a conclusion of the workshop.
Hypoxia-inducible Factor 1α Induces Corticosteroid-insensitive Inflammation via Reduction of Histone Deacetylase-2 Transcription
Publisher: Elsevier BV
Date: 12-2009
Targeting Phosphoinositide-3-Kinase-δ with Theophylline Reverses Corticosteroid Insensitivity in Chronic Obstructive Pulmonary Disease
Publisher: American Thoracic Society
Date: 10-2010
Epigenetic regulation of airway inflammation
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.COI.2007.07.016
Abstract: Diverse cellular functions including the regulation of inflammatory gene expression, DNA repair and cell proliferation are regulated by epigenetic changes. Transcriptional co-activators possess intrinsic histone acetyltransferase (HAT) activity, and histone acetylation plays a major role in inflammatory gene expression. Other marks such as histone methylation are also associated with gene induction and gene repression. Recent evidence implicates histone acetylation and methylation as being crucial for the development of tolerance in macrophages and CpG methylation for T regulatory cell development and function. The expression of the enzymes that lay down or remove these epigenetic marks have not been well studied in human airways disease, but reduced HDAC2 expression and activity is reported in lung macrophages, biopsies and blood cells from patients with COPD, severe asthma and smoking asthma. In vitro, inhibitors of histone deacetylases (HDAC) often lead to a further induction of inflammatory gene expression. This is not always the case, however, as HATs and HDACs also target non-histone proteins particularly transcription factors to alter their activity. Furthermore, trichostatin A, an HDAC inhibitor, can reduce inflammation in a murine model of allergic asthma. This effect of HDAC inhibitors may be due to their effects on cell death acting through acetylation of non-histone proteins. The role of epigenetic modifications in inflammatory gene expression and in the control of cell function in the airways is becoming clearer. Targeting specific enzymes involved in this process may lead to new therapeutic agents, in particular, in situations where current anti-inflammatory therapies are currently suboptimal.
T Helper Cell Subsets in the Pleural Fluid of Tuberculous Patients Differentiate Patients With Non-Tuberculous Pleural Effusions
Publisher: Frontiers Media SA
Date: 02-12-2021
DOI: 10.3389/FIMMU.2021.780453
Abstract: Tuberculous pleural effusion (TPE) is one of the most common forms of extrapulmonary tuberculosis (Tb). Patients with TPE or malignant pleural effusions (MPE) frequently have a similar lymphocytic pleural fluid profile. Since the etiology of PE in various diseases is different, identifying the cellular components may provide diagnostic clues for understanding the pathogenesis. We determined the frequency of T helper (Th) subtypes in the PEs for differentiation of Tb and non-Tb patients. Thirty patients with TPE, 30 patients with MPE, 14 patients with empyema (EMP), and 14 patients with parapneumonic effusion (PPE) were enrolled between December 2018 and December 2019. Five-milliliter fresh PE in tubes containing heparin as an anticoagulant was obtained from patients. The frequencies of CD4+IL-9+, CD4+IL-22+, CD+IL-17+, and regulatory T-cells CD4+CD25+ FOXP3+ (Treg) were determined by flow cytometry. Treg cells have a lower frequency in TPE patients [4.2 (0.362–17.24)] compared with non-TPE patients [26.3 (3.349–76.93, p & 0.0001)]. The frequency of CD4+IL-9+ cells was significantly lower in TPE patients [3.67 (0.87–47.83)] compared with non-TPE groups [13.05 (1.67–61.45), p & 0.0001]. On the contrary, there was no significant difference in the frequency of CD4+IL-17+ and CD4+IL-22+ cells between TPE and non-TPE patients (p = 0.906 and p = 0.2188). Receiver-operator curve (ROC) analysis demonstrated that CD4+CD25+FOXP3+ T cells [optimal cutoff value = 13.6 (%), sensitivity 90%, specificity 75.86%] could be considered as predictor for TPE. However, adenosine deaminase [cutoff value 27.5 (IU/l), sensitivity 90%, specificity 96.5%] levels had an even greater predictive capacity. ADA, Treg cells, and CD4+IL-9+ cells may differentiate TPE from non-TPE patients. However, these results need validation in an independent large cohort.
Do Low-density Granulocytes Induce Lymphopenia in Patients with COVID-19?
Publisher: Knowledge E DMCC
Date: 21-06-2022
DOI: 10.18502/IJAAI.V21I3.9811
Abstract: The Article Abstract is not available.
Stratified treatment of localized cervical esophageal squamous cell carcinoma induced by neoadjuvant immunotherapy plus chemotherapy (SCENIC)
Publisher: AME Publishing Company
Date: 09-2022
DOI: 10.21037/JTD-22-402
The Journal of Inflammation
Publisher: Springer Science and Business Media LLC
Date: 2004
Sarcoidosis: Role of non-tuberculosis mycobacteria and Mycobacterium tuberculosis
Publisher: Medknow
Date: 12-2014
DOI: 10.1016/J.IJMYCO.2014.10.008
Abstract: Sarcoidosis is a granulomatous inflammatory disease that is induced by unknown antigen(s) in a genetically susceptible host. Although the direct link between Mycobacterium tuberculosis (MTB) infection and sarcoidosis can be excluded on the basis of current knowledge, non-infectious mechanisms may explain the causative role of mycobacterial antigens. Ever since sarcoidosis was first described, its relationship with tuberculosis (TB) has been under-investigated. Whereas some researchers consider sarcoidosis and TB as two ex les of the same disease process, others have rejected mycobacteria as playing any causative role in sarcoidosis. Whether they are linked causally or not, clinical evidence makes a differential diagnosis between the two conditions very challenging, particularly in countries with high burden of TB. The present study analyzes the relationship between sarcoidosis and TB and its implications in clinical practice. The coincidence of TB and sarcoidosis and the higher incidence of mycobacterial DNA in biological s les of sarcoid patients have been reported by many authors. In addition, new evidence of a similarity in MTB phenotype in sarcoidosis is provided. Overall, these observations suggest that TB and sarcoidosis may not only share the same etiology, but may even be different aspects of one disease.
Impact of protein acetylation in inflammatory lung diseases
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.PHARMTHERA.2007.06.009
Abstract: Chronic inflammatory lung diseases are characterized by increased expression of multiple inflammatory genes following activation by proinflammatory transcription factors, such as nuclear factor kappaB (NF-kappaB) and AP-1. Gene expression is, at least in part, regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein (CBP), which have intrinsic histone acetyltransferase (HAT) activity. Conversely gene repression is mediated via a combination of histone deacetylases (HDAC) and other corepressors. In asthma, the level of HAT activity is elevated in bronchial biopsies, whereas HDAC activity levels are only partially reduced and inhaled corticosteroids are able to reduce the increased HAT activity back to those seen in normal subjects. In contrast, in chronic obstructive pulmonary disease (COPD), there is a greater reduction in HDAC activity and HDAC2 expression but no difference in HAT activity. HAT and HDAC are also reported to modify a large and expanding number of nonhistone proteins, including nuclear import proteins, chaperones, cytoskeletal proteins, and other transcriptional factors, such as NF-kappaB and signal transducer and activation of transcription (STAT). Acetylation regulates several aspects of protein function and stability leading to differing effects on inflammatory gene expression and cell recruitment involved in the pathogenesis of inflammatory diseases. This review will examine the impact of acetylation on the function of key proteins involved in airway inflammatory disease and the effects of current therapies on acetylation status of key proteins. Further appreciation of the role of these changes may lead to the development of novel therapeutic approaches to inflammatory lung diseases that are currently difficult to treat.
Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study
Publisher: European Respiratory Society (ERS)
Date: 06-10-2016
DOI: 10.1183/13993003.01129-2016
Abstract: The U-BIOPRED study is a multicentre European study aimed at a better understanding of severe asthma. It included three steroid-treated adult asthma groups (severe nonsmokers (SAn group), severe current/ex-smokers (SAs/ex group) and those with mild–moderate disease (MMA group)) and healthy controls (HC group). The aim of this cross-sectional, bronchoscopy substudy was to compare bronchial immunopathology between these groups. In 158 participants, bronchial biopsies and bronchial epithelial brushings were collected for immunopathologic and transcriptomic analysis. Immunohistochemical analysis of glycol methacrylate resin-embedded biopsies showed there were more mast cells in submucosa of the HC group (33.6 mm −2 ) compared with both severe asthma groups (SAn: 17.4 mm −2 , p .001 SAs/ex: 22.2 mm −2 , p=0.01) and with the MMA group (21.2 mm −2 , p=0.01). The number of CD4 + lymphocytes was decreased in the SAs/ex group (4.7 mm −2 ) compared with the SAn (11.6 mm −2 , p=0.002), MMA (10.1 mm −2 , p=0.008) and HC (10.6 mm −2 , p .001) groups. No other differences were observed. Affymetrix microarray analysis identified seven probe sets in the bronchial brushing s les that had a positive relationship with submucosal eosinophils. These mapped to COX-2 (cyclo-oxygenase-2), ADAM-7 (disintegrin and metalloproteinase domain-containing protein 7), SLCO1A2 (solute carrier organic anion transporter family member 1A2), TMEFF2 (transmembrane protein with epidermal growth factor like and two follistatin like domains 2) and TRPM-1 (transient receptor potential cation channel subfamily M member 1) the remaining two are unnamed. We conclude that in nonsmoking and smoking patients on currently recommended therapy, severe asthma exists despite suppressed tissue inflammation within the proximal airway wall.
The glucocorticoid RU24858 does not distinguish between transrepression and transactivation in primary human eosinophils
Publisher: Springer Science and Business Media LLC
Date: 12-07-2006
Abstract: Glucocorticoids are used to treat chronic inflammatory diseases such as asthma. Induction of eosinophil apoptosis is considered to be one of the main mechanisms behind the anti-asthmatic effect of glucocorticoids. Glucocorticoid binding to its receptor (GR) can have a dual effect on gene transcription. Activated GR can activate transcription (transactivation), or by interacting with other transcription factors such as NF-κB suppress transcription (transrepression). RU24858 has been reported to transrepress but to have little or no transactivation capability in other cell types. The dissociated properties of RU24858 have not been previously studied in non-malignant human cells. As the eosinophils have a very short lifetime and many of the modern molecular biological methods cannot be used, a "dissociated steroid" would be a valuable tool to evaluate the mechanism of action of glucocorticoids in human eosinophils. The aim of this study was to elucidate the ability of RU24858 to activate and repress gene expression in human eosinophils in order to see whether it is a dissociated steroid in human eosinophils. Human peripheral blood eosinophils were isolated under sterile conditions and cultured in the presence and/or absence RU24858. For comparison, dexamethasone and mometasone were used. We measured chemokine receptor-4 (CXCR4) and Annexin 1 expression by flow cytometry and cytokine production by ELISA. Apoptosis was measured by DNA fragmentation and confirmed by morphological analysis. RU24858 (1 μM) increased CXCR4 and Annexin 1 expression on eosinophils to a similar extent as mometasone (1 μM) and dexamethasone (1 μM). Like dexamethasone and mometasone, RU24858 did suppress IL-8 and MCP-1 production in eosinophils. RU24858 also increased spontaneous eosinophil apoptosis to a similar degree as dexamethasone and mometasone, but unlike dexamethasone and mometasone it did not reverse IL-5- or GM-CSF-induced eosinophil survival. Our results suggest that in human eosinophils RU24858 acts as transactivator and transrepressor like classical glucocorticoids. Thus, RU24858 seems not to be a "dissociated steroid" in primary human eosinophils in contrast to that reported in animal cells. In addition, functionally RU24858 seems to be a less potent glucocorticoid as it did not reverse IL-5- and GM-CSF-afforded eosinophil survival similarly to dexamethasone and mometasone.
Nuclear Factor κ-B Is Activated in the Pulmonary Vessels of Patients with End-Stage Idiopathic Pulmonary Arterial Hypertension
Publisher: Public Library of Science (PLoS)
Date: 04-10-2013
Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.RMED.2019.02.008
Abstract: Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MS
Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK)
Publisher: BMJ
Date: 23-07-2015
Mitochondrial function in three different types of airway epithelial cells
Publisher: European Respiratory Society
Date: 09-2015
Role of Mast Cells and Type 2 Innate Lymphoid (ILC2) Cells in Lung Transplantation
Publisher: Hindawi Limited
Date: 30-10-2018
DOI: 10.1155/2018/2785971
Abstract: The multifunctional role of mast cells (MCs) in the immune system is complex and has not fully been explored. MCs reside in tissues and mucous membranes such as the lung, digestive tract, and skin which are strategically located at interfaces with the external environment. These cells, therefore, will encounter external stimuli and pathogens. MCs modulate both the innate and the adaptive immune response in inflammatory disorders including transplantation. MCs can have pro- and anti-inflammatory functions, thereby regulating the outcome of lung transplantation through secretion of mediators that allow interaction with other cell types, particularly innate lymphoid cells (ILC2). ILC2 cells are a unique population of hematopoietic cells that coordinate the innate immune response against a variety of threats including infection, tissue damage, and homeostatic disruption. In addition, MCs can modulate alloreactive T cell responses or assist in T regulatory (Treg) cell activity. This paper outlines the current understanding of the role of MCs in lung transplantation, with a specific focus on their interaction with ILC2 cells within the engrafted organ.
Immunophenotype and function of circulating myeloid derived suppressor cells in COVID-19 patients
Publisher: Springer Science and Business Media LLC
Date: 29-12-2022
DOI: 10.1038/S41598-022-26943-Z
Abstract: The pathogenesis of coronavirus disease 2019 (COVID-19) is not fully elucidated. COVID-19 is due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes severe illness and death in some people by causing immune dysregulation and blood T cell depletion. Increased numbers of myeloid-derived suppressor cells (MDSCs) play a erse role in the pathogenesis of many infections and cancers but their function in COVID-19 remains unclear. To evaluate the function of MDSCs in relation with the severity of COVID-19. 26 PCR-confirmed COVID-19 patients including 12 moderate and 14 severe patients along with 11 healthy age- and sex-matched controls were enrolled. 10 ml whole blood was harvested for cell isolation, immunophenotyping and stimulation. The immunophenotype of MDSCs by flow cytometry and T cells proliferation in the presence of MDSCs was evaluated. Serum TGF-β was assessed by ELISA. High percentages of M-MDSCs in males and of P-MDSCs in female patients were found in severe and moderate affected patients. Isolated MDSCs of COVID-19 patients suppressed the proliferation and intracellular levels of IFN-γ in T cells despite significant suppression of T regulatory cells but up-regulation of precursor regulatory T cells. Serum analysis shows increased levels of TGF-β in severe patients compared to moderate and control subjects (HC) (P = 0.003, P 0.0001, respectively). The frequency of MDSCs in blood shows higher frequency among both moderate and severe patients and may be considered as a predictive factor for disease severity. MDSCs may suppress T cell proliferation by releasing TGF-β.
Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma
Publisher: Wiley
Date: 10-09-2019
DOI: 10.1111/ALL.14016
Abstract: Whether the clinical or pathophysiologic significance of the “treatable trait” high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma. Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U‐BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U‐BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil 200 cells/μL as a cut‐off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values). There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U‐BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.
High-fat diet in mice leads to amplified ozone-induced airway hyperresponsiveness (AHR), mitochondrial dysfunction and insulin resistance
Publisher: European Respiratory Society
Date: 09-2016
Pharmacology of airway inflammation in asthma and COPD
Publisher: Elsevier BV
Date: 10-2003
Severity of acute respiratory distress syndrome resulting from tuberculosis correlates with bronchoalveolar lavage CXCL-8 expression
Publisher: Medknow
Date: 03-2015
Anti-Inflammatory Mechanisms of Glucocorticoids Targeting Granulocytes
Publisher: Bentham Science Publishers Ltd.
Date: 08-2005
Abstract: Asthmatic inflammation involves the recruitment and activation of inflammatory cells, and changes in the structural cells of the lung and asthma are characterized by an increased expression of components of the inflammatory cascade including cytokines, chemokines, growth factors, enzymes, receptors and adhesion molecules. The increased expression of these proteins seen in asthma is generally the result of enhanced gene transcription, since many of the genes are not expressed in normal cells but are induced in a cell-specific manner during the inflammatory process. There is clear evidence that neutrophils, long thought of as being transcriptionally inert, can respond to stimuli to induce inflammatory genes. Glucocorticoids are very effective in controlling the inflammation seen in asthmatic airways. Beyond their recognized actions on eosinophil and neutrophil apoptosis, glucocorticoids have profound effects on the chemotaxis, activation and release of mediators from granulocytes (eosinophils, neutrophils and basophils). Few mechanistic studies are available in these cells, but it appears that in granulocytes, glucocorticoids target the same signaling pathways, such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), that are important in other cells. We summarize these known mechanisms at the end of this review.
P29 Endothelial cell NF-kB activation is increased in human idiopathic PAH
Publisher: BMJ
Date: 16-11-2010
Corticosteroid modulation of immunoglobulin expression and B‐cell function in COPD
Publisher: Wiley
Date: 17-02-2016
DOI: 10.1096/FJ.201500135
Abstract: We investigated changes in gene expression that occur in chronic obstructive pulmonary disease (COPD) after corticosteroid treatment and sought to identify the mechanisms that regulate these changes. Biopsy s les were taken from patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage I to II) before and after treatment with fluticasone propionate (FP)/salmeterol (SM) (50/500, 4 wk). Gene expression was measured by microarray and was confirmed by real-time reverse transcription-quantitative PCR (RT-qPCR). The effect of FP on IgG expression and B-cell proliferation in the presence of oxidative stress was also studied. FP/SM significantly increased the expression of 180 genes while repressing 343 genes. The top 5 down-regulated genes were associated with immunoglobulin production, whereas the immunomodulatory FK506 binding protein (FK506BP) was up-regulated. Genes including IL6, IL8, and TBET-encoding TBX21 were unaffected. FP reduced IgG protein and mRNA expression and proliferation of human B cells through the dephosphorylation of ERK-1/2 via increased DUSP1 (dual-specificity protein phosphatase 1) expression. Consistent with in vivo data, oxidative stress did not prevent FP-induced suppression of IgG expression in human B cells in vitro Changes in expression were validated by RT-qPCR and by gene set enrichment analysis in distinct COPD cohorts. FP may reduce the adaptive immune response in COPD and may be more effective in patients with an increased B-cell/antibody response indicated by high autoantibody titers.-Lee, J., Machin, M., Russell, K. E., Pavlidis, S., Zhu, J., Barnes, P. J., Chung, K. F., Adcock, I. M., Durham, A. L. Corticosteroid modulation of immunoglobulin expression and B-cell function in COPD.
Role of CBP in glucocorticoid-induced gene repression
Publisher: Portland Press Ltd.
Date: 08-1998
DOI: 10.1042/BST026S255
Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk
Publisher: American Thoracic Society
Date: 15-07-2023
Characterisation of a novel 3D model of the airways
Publisher: European Respiratory Society
Date: 09-2015
Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration
Publisher: Elsevier BV
Date: 02-2004
Immunologic finding of disseminated granuloma reaction in patients with Mycobacterium tuberculosis and sarcoidosis
Publisher: Medknow
Date: 03-2015
First report of occurrence of Mycobacterium tuberculosis and Non-tuberculous mycobacteria in a heterozygous carrier of chronic granulomatous patient
Publisher: Medknow
Date: 03-2015
Single‐Nucleotide Polymorphisms Associated with Symptomatic Infection and Differential Human Gene Expression in Healthy Seropositive Persons Each Implicate the Cytoskeleton, Integrin Signaling, and On
Publisher: Oxford University Press (OUP)
Date: 15-07-2005
DOI: 10.1086/430950
Abstract: This study was undertaken to further examine the role of the host response to parvovirus B19 in the development of symptoms and consequences of viral persistence. Genomic DNA from 42 patients with symptomatic B19 infection was analyzed using the HuSNP assay (Affymetrix), and the results were compared with those from analysis of 53 healthy control in iduals. Fifty-seven single-nucleotide polymorphisms were identified that were significantly associated with symptomatic infection. Total RNA from peripheral blood mononuclear cells from 57 B19-seropositive and 13 B19-seronegative donors was analyzed by hybridization to a single-color microarray representing 9522 human genes. Ninety-two genes were shown to be differentially expressed. Differential expression was confirmed in 6 of 38 genes (SKIP, MACF1, SPAG7, FLOT1, c6orf48, and RASSF5) tested using real-time quantitative polymerase chain reaction in a different group of healthy subjects. Genes identified in both studies play a functional role in the cytoskeleton, integrin signaling, and oncosuppression, themes that have been shown to be important in parvovirus infections.
The effects of chronic psychological stress on the immune response to lymphoma (#2098)
Publisher: Wiley
Date: 08-2016
Low‐frequency ventilation during cardiopulmonary bypass for lung protection: A randomized controlled trial
Publisher: Hindawi Limited
Date: 02-05-2019
DOI: 10.1111/JOCS.14044
Abstract: Pulmonary dysfunction is a common complication in patients undergoing heart surgery. Current clinical practice does not include any specific strategy for lung protection. To compare the anti-inflammatory effects of low-frequency ventilation (LFV), as measured by nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) p65 pathway activation, for the entire cardiopulmonary bypass (CPB) vs both lungs left collapsed in patients undergoing coronary artery bypass grafting (CABG). Two groups parallel randomized controlled trial. The primary outcome was inflammation measured by NF-κB p65 activation in pre- and post-CPB lung biopsies. Secondary outcomes were additional inflammatory markers in both biopsy tissue and blood. Thirty-seven patients were randomly allocated to LFV (18) and to both lungs left collapsed (19). The mean concentration of NF-κB p65 in the biopsies before chest closure (adjusted for pre-CPB concentration) was higher in the LFV group compared to both lungs left collapsed group but this was not significant (0.102, 95% confidence interval, -0.022 to 0.226, P = 0.104). There were no significant differences between groups in the other inflammatory markers measured in tissue and blood. In patients undergoing elective CABG, the use of LFV during CPB when compared to both lungs left collapsed does not seem to reduce inflammation in lung biopsies and blood.
Host-microbe cross-talk in the lung microenvironment: implications for understanding and treating chronic lung disease
Publisher: European Respiratory Society (ERS)
Date: 19-05-2020
DOI: 10.1183/13993003.02320-2019
Abstract: Chronic respiratory diseases are highly prevalent worldwide and will continue to rise in the foreseeable future. Despite intensive efforts over the recent decades, the development of novel and effective therapeutic approaches has been slow. There is however new and increasing evidence that communities of microorganisms in our body, the human microbiome, are crucially involved in the development and progression of chronic respiratory diseases. Understanding the detailed mechanisms underlying this cross-talk between host and microbiota is critical for development of microbiome- or host-targeted therapeutics and prevention strategies. Here we review and discuss the most recent knowledge on the continuous reciprocal interaction between the host and microbes in health and respiratory disease. Furthermore, we highlight promising developments in microbiome-based therapies and discuss the need to employ more holistic approaches of restoring both the pulmonary niche and the microbial community.
Urinary metabolomics-profiling of the U-BIOPRED asthma study identified biochemical clusters associated with asthma severity
Publisher: European Respiratory Society
Date: 07-09-2020
Immune modulation via T regulatory cell enhancement: Disease‐modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases—An EAACI position paper of the Task
Publisher: Wiley
Date: 2021
DOI: 10.1111/ALL.14478
Abstract: Therapeutic advances using targeted biologicals and small‐molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment‐resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell–based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell–based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell–based approaches, especially Treg‐based approaches, in severe IgE‐mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment‐resistant forms of these immune‐driven disorders.
Molecular Mechanisms of Glucocorticosteroid Actions
Publisher: Elsevier BV
Date: 06-2000
Sputum metagenomics of U-BIOPRED asthma cohort: link to severity and granulocytic inflammation
Publisher: European Respiratory Society
Date: 04-09-2022
Cytokine inhibition in the treatment of COPD
Publisher: Informa UK Limited
Date: 04-2014
DOI: 10.2147/COPD.S42544
Misuse of investigations in community acquired pneumonia at Logan Hospital
Publisher: Wiley
Date: 03-2022
DOI: 10.1111/RESP.14226
PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD)
Publisher: Springer Science and Business Media LLC
Date: 12-2018
The roles of miRNAs as potential biomarkers in lung diseases
Publisher: Elsevier BV
Date: 11-2016
Zymosan attenuates melanoma growth progression, increases splenocyte proliferation and induces TLR-2/4 and TNF-α expression in mice
Publisher: Springer Science and Business Media LLC
Date: 22-03-2018
Abnormal histone acetylase and deacetylase expression and function in lung inflammation
Publisher: Springer Science and Business Media LLC
Date: 08-2006
DOI: 10.1007/S00011-006-0081-1
Abstract: Post-translational modifications in DNA and histone proteins are heritable changes that are not coded for in the DNA sequence itself but play an important role in the control of gene expression. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. These changes are not only critical for generating ersity of cell types during mammalian development, but are also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that altered patterns of histone modifications can lead to several major pathologies. This review focuses on histone acetylation and its role in inflammatory gene expression. Interestingly, the expression and activity of enzymes that regulate this modification have been reported to be abnormal in the airways of patients with respiratory disease. Histone modifications, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of "epigenetic therapies" for disease.
Asthma phenotypes and T-bet protein expression in cells treated with Fluticasone Furoate/Vilanterol
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.PUPT.2020.101886
Abstract: Asthma is a complex disease with erse clinical manifestations ranging from mild to severe. Despite existing guidelines for asthma recognition and treatment, still a proportion of patients stay uncontrolled. Combinational therapy which comprises inhaled corticosteroids (ICS) and a long acting B2 adrenreceptor agonist (LABA) has been suggested to control asthma. In this study T-bet expression was attested in CD4 T cells treated with Fluticasone Furoate (FF), Vilanterol (V) and FF/V combination in severe asthmatic patients compared to patients with moderate asthma and healthy controls using Immunocytochemistry (ICC). First, CD4 T cells were isolated from PBMCs of 12 patients and controls using CD4 T cell isolation kit. Subsequently, isolated CD4 T cells were cultured with FF, V and FF/V for 1 h. To accomplish ICC, cells were incubated with anti-T-bet antibody, and then stained with HRP-bound secondary antibody. T-bet expression was evaluated using light microscopy. Statistical analyses were performed using R 3.5.2 software and visualized by ggplot2 3.1.0 package. Significant increasing in T-bet expression was seen in CD4 T cells from patients with moderate asthma treated with FF and FF/V. Suggesting conclusion would be distinct mechanisms responsible for severe asthma and moderate asthma in the patients and the needs for novel therapies. Further molecular studies in different asthma phenotypes would be instructive for asthma treatment.
Multi-omic analysis of the effects of low frequency ventilation during cardiopulmonary bypass surgery
Publisher: Elsevier BV
Date: 06-2020
Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.JACI.2017.02.045
Abstract: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. We sought to determine differential gene and protein expression in sputum s les from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13-induced T IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. T
Bacterial infections in the lungs of patients with systemic autoimmune diseases
Publisher: Elsevier
Date: 2020
Gene signatures from U-BIOPRED transcriptomic-associated clusters exist in COPD
Publisher: European Respiratory Society
Date: 09-2017
Corticosteroid Resistance and Novel Anti-Inflammatory Therapies in Chronic Obstructive Pulmonary Disease
Publisher: Springer Science and Business Media LLC
Date: 07-2012
DOI: 10.2165/11634350-000000000-00000
Abstract: Corticosteroids are widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, in contrast to their use in mild-to-moderate asthma, they are much less effective in enhancing lung function and have little or no effect on controlling the underlying chronic inflammation. In most clinical trials in COPD patients, corticosteroids have shown little benefit as monotherapy, but have shown a greater clinical effect in combination with long-acting bronchodilators. Several mechanisms of corticosteroid resistance have been postulated, including a reduction in histone deacetylase (HDAC)-2 activity and expression, impaired corticosteroid activation of the glucocorticoid receptor (GR) and increased pro-inflammatory signalling pathways. Reversal of corticosteroid resistance in COPD patients by restoring HDAC2 levels has proved effective in a small study, and long-term studies are needed to determine whether novel HDAC2 activators or theophylline improve disease progression, exacerbations or mortality. Advances in the understanding of the cellular and molecular mechanisms of corticosteroid resistance in COPD pathophysiology have supported the development of new emerging classes of anti-inflammatory drugs in COPD treatment. These include treatments such as inhibitors of phosphoinositide-3-kinase-delta (PI3Kδ), phosphodiesterase-4 (PDE4), p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), and therapeutic agents such as chemokine receptor antagonists. Of these, PI3Kδ, PDE4, p38 MAPK inhibitors and chemokine receptor antagonists are in clinical patient trials. Of importance, patient adverse effects associated with oral administration of these novel agents needs to be addressed in order to optimize therapy and patient compliance. Combinations of these drugs with corticosteroids may have additional benefits.
Chronic Obstructive Pulmonary Disease and Lung Cancer: New Molecular Insights
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000324601
Abstract: Both chronic obstructive pulmonary disease (COPD) and lung cancer are major causes of death worldwide. In most cases this reflects cigarette smoke exposure which is able to induce an inflammatory response in the airways of smokers. Indeed, COPD is characterized by lower airway inflammation, and importantly, the presence of COPD is by far the greatest risk factor for lung cancer amongst smokers. Cigarette smoke induces the release of many inflammatory mediators and growth factors including TGF-β, EGFR, IL-1, IL-8 and G-CSF through oxidative stress pathways and this inflammation may persist for decades after smoking cessation. Mucus production is also increased by these inflammatory mediators, further linking airway inflammation to an important mechanism of lung cancer. A greater understanding of the molecular and cellular pathobiology that distinguishes smokers with lung cancer from smokers with and without COPD is needed to unravel the complex molecular interactions between COPD and lung cancer. By understanding the common signalling pathways involved in COPD and lung cancer the hope is that treatments will be developed that not only treat the underlying disease process in COPD, but also reduce the currently high risk of developing lung cancer in these patients.
Glucocorticoid-mediated transrepression is regulated by histone acetylation and DNA methylation
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1016/S0014-2999(01)01332-2
Abstract: Glucocorticoids are highly effective in controlling chronic inflammatory diseases by inhibiting the expression of cytokines and chemokines. Glucocorticoids act through binding of their receptor resulting to inhibition of transcription factors such as nuclear factor kappa B (NF-kappa B). This may occur via the transcription integrator protein, CREB binding protein (CBP), which has intrinsic histone acetylase (HAT) activity. Interleukin (IL)-1 beta caused a significant increase in NF-kappa B-mediated granulocyte/macrophage colony stimulating factor (GM-CSF) release, which was inhibited by the glucocorticoid mometasone furoate (MF) (EC(50)=2 x 10(-11) M). This effect was inhibited by CBP over-expression. The role of histone acetylation and DNA methylation in the transcription of GM-CSF was indicated by trichostatin A (TSA), an inhibitor of histone deacetylases, and 5-azacytidine (5-aza), a DNA methylase inhibitor, to increase GM-CSF expression partially blocking glucocorticoid inhibition of IL-1 beta-stimulated GM-CSF release. These data suggest that the mechanism of glucocorticoid action in suppressing interleukin-1 beta-stimulated GM-CSF release in A549 cells may involve modulation of CBP-mediated histone-acetylase activity and DNA methylation.
Gene–environment interactions in the development of chronic obstructive pulmonary disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2006
Possible cancer-causing capacity of COVID-19: Is SARS-CoV-2 an oncogenic agent?
Publisher: Elsevier BV
Date: 10-2023
Long-acting fluticasone furoate has a superior pharmacological profile to fluticasone propionate in human respiratory cells
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.EJPHAR.2011.08.022
Abstract: Currently available glucocorticoids are relatively short acting and may be less effective in patients with chronic obstructive pulmonary disease (COPD) where high levels of oxidative stress are seen. Here we show that a novel glucocorticoid, fluticasone furoate (FF), has a longer duration of action in several cell systems compared with fluticasone propionate (FP) and budesonide, and unlike FP, FF is resistant to oxidative stress. FF had similar or slightly higher potency to FP and was 2-9 fold more potent than budesonide, when assessed at 4h, in inhibiting inflammatory cytokine production in epithelial cell lines (BEAS2B, A549), primary bronchial epithelial cells and a monocytic cell line (U937). The potency of FF was sustained beyond 16 h with or without washout compared with FP or budesonide, such that it showed a greater duration of action in this range of cellular assays. The activated YFP-conjugated glucocorticoid receptor was detectable in nuclei of FF treated BEAS2B cells for at least for 30 h, and FF had a longer duration of action than FP in inhibiting activation of transcription factors such as NF-κB and AP-1. In addition, FF showed superior effects to FP in peripheral blood mononuclear cells from patients with COPD and also in U937 cells or primary bronchial epithelial cells under conditions of oxidative stress. The longer duration of action and oxidative stress insensitivity of FF compared with FP has potential clinical implications for the control of inflammation in respiratory diseases, such as COPD.
Evidence for Involvement of NF-κB in the Transcriptional Control of COX-2 Gene Expression by IL-1β
Publisher: Elsevier BV
Date: 08-1997
Abstract: The cyclooxygenase (COX) isoforms COX-1 and COX-2 convert arachidonic acid to prostaglandin (PG) precursors and are a limiting step in PG production. Interleukin-1beta (IL-1beta) treatment of type II A549 cells increases PGE2 synthesis via transcription- and translation-dependent induction of COX-2. IL-1beta produces a 10-fold induction of COX-2 mRNA and an 8-fold increase in COX-2 transcription that was temporally preceded by activation of the transcription factor nuclear factor-kappaB (NF-kappaB). The protein-tyrosine phosphatase inhibitor phenylarsine oxide (PAO) prevented both NF-kappaB activation and induction of COX-2 mRNA. We show that two putative NF-kappaB motifs, kappaBu (-447/-438) and kappaBd (-224/-214), from the COX-2 promoter bind p50 65 NF-kappaB heterodimers in an IL-1beta-dependent manner and that the upstream element has the greater affinity. Finally, we demonstrate that the two NF-kappaB subunits, p50 and p65, synergistically activate a -917/+49 COX-2 promoter construct. We conclude that IL-1beta stimulates PG production via transcriptional activation of COX-2 and provide evidence that this may involve NF-kappaB.
A Severe Asthma Disease Signature from Gene Expression Profiling of Peripheral Blood from U-BIOPRED Cohorts
Publisher: American Thoracic Society
Date: 15-05-2017
Abnormal histone acetylase and deacetylase expression and function in lung inflammation
Publisher: Springer Science and Business Media LLC
Date: 12-2006
Adult Severe Asthma
Publisher: Elsevier
Date: 2022
Role of TLR2, TLR4, and MyD88 in murine ozone-induced airway hyperresponsiveness and neutrophilia
Publisher: American Physiological Society
Date: 10-2007
DOI: 10.1152/JAPPLPHYSIOL.00172.2007
Abstract: Exposure to air pollutants such as ozone (O 3 ) induces airway hyperresponsiveness (AHR) and airway inflammation. Toll-like receptors (TLR) are first-line effector molecules in innate immunity to infections and signal via adapter proteins, including myeloid differentiation factor-88 (MyD88). We investigated the sensing of ozone by TLR2, TLR4, and MyD88. Ozone induced AHR in wild-type (WT) C57BL/6 mice, but AHR was absent in TLR2 −/− , TLR4 −/− , and MyD88 −/− mice. Bronchoalveolar lavage neutrophilia induced by ozone was inhibited at 3 h but not at 24 h in TLR2 −/− and TLR4 −/− mice, while in MyD88 −/− mice, this was inhibited at 24 h. We investigated the expression of inflammatory cytokines and TLR2, TLR4, and MyD88 in these mice. Ozone induced time-dependent increases in inflammatory gene expression of keratinocyte chemoattractant (KC) and IL-6 and of TLR2, TLR4, and MyD88 in WT mice. IL-6 and KC expression induced by ozone was inhibited in TLR2 −/− , TLR4 −/− , and MyD88 −/− mice. Expression of MyD88 was increased in TLR2 −/− and TLR4 −/− mice, while induction of TLR2 or TLR4 was reduced in TLR2 −/− and TLR4 −/− mice, respectively. TLR2 and TLR4 mediate AHR induced by oxidative stress such as ozone, while the adapter protein MyD88, but not TLR2 or TLR4, is important in mediating ozone-induced neutrophilia. TLR2 and TLR4 may also be important in regulating the speed of neutrophilic response. Therefore, ozone may induce murine AHR and neutrophilic inflammation through the activation of the Toll-like receptor pathway that may sense noninfectious stimuli such as oxidative stress.
Mitogen-Activated Protein Kinase Modulation of Nuclear Factor-κB–Induced Granulocyte Macrophage–Colony-Stimulating Factor Release from Human Alveolar Macrophages
Publisher: American Thoracic Society
Date: 03-2004
Glucocorticoid Pathways in Chronic Obstructive Pulmonary Disease Therapy
Publisher: American Thoracic Society
Date: 11-2005
Evaluation Expression of miR-146a and miR-155 in Non-Small-Cell Lung Cancer Patients
Publisher: Frontiers Media SA
Date: 11-2021
Abstract: Non−small-cell lung cancer (NSCLC) is the major type of lung cancer. MicroRNAs (miRNAs) are novel markers and targets in cancer therapy and can act as both tumor suppressors and oncogenes and affect immune function. The aim of this study was to investigate the expression of miR146a and miR155 in linked to blood immune cell phenotypes and serum cytokines in NSCLC patients. Thirty-three NSCLC patients and 30 healthy subjects were enrolled in this study. The allele frequencies of potential DNA polymorphisms were studied using polymerase chain reaction (PCR)–restriction fragment length polymorphism (PCR-RFLP) analysis in peripheral blood s les. Quantitative reverse transcription PCR (qRT-PCR) was used to measure the expression of miR-146a and miR-155 in peripheral blood mononuclear cells (PBMCs). Serum cytokine (IL-1β, IL-6, TNF-α, TGF-β, IL-4, IFN-γ) levels were determined by ELISA. The frequency of circulating CD3+CTLA-4+ and CD4+CD25+FOXP3+ (T regulatory cells/Treg) expression was measured by flow cytometry. miR-146a was significantly downregulated in PBMC of NSCLC patients (P ≤ 0.001). Moreover, IL-6 and TGF-β levels were elevated in NSCLC patients (P ≤ 0.001, P ≤ 0.018, respectively). CD3+ CTLA-4+ and Treg cells frequencies were higher in patients than in control subjects (P ≤ 0.0001, P ≤ 0.0001, respectively). There was a positive correlation between miR-155 and IL-1β levels (r=0.567, p ≤ 0.001) and a negative correlation between miR-146a and TGF-β levels (r=-0.376, P ≤ 0.031) in NSCLC patients. No significant differences were found in the relative expression of miR-146a and miR-155, cytokine levels or immune cell numbers according to miR-146a and miR-155 (GG/GC/CC, TT/AT/AA) genotypes. However, there was a positive correlation between miR-146a and IL-1β levels (r=0.74, P ≤ 0.009) in GG subjects and a positive correlation between miR-146a expression and CD3+CTLA4+ cell frequency (r=0.79, P ≤ 0.01) in CC genotyped subjects. Conversely, a negative correlation between miR-146a expression and Treg cell frequency (r=−0.87, P ≤ 0.05) was observed with the GG genotype. A positive correlation between miR-155 and IL-1β expression (r=0.58, p ≤ 0.009) in the TT genotype and between miR-155 expression and CD3+CTLA-4 cell frequency (r=0.75, P ≤ 0.01) was observed in the AT genotype. The current data suggest that the miR-146a expression in PBMC and serum TGF-β and IL-1β levels may act as blood markers in NSCLC patients. Further study is needed to elucidate the link between immune cells and serum miR146 at early disease stages.
Hydrogen Peroxide Prolongs Nuclear Localization of NF-κB in Activated Cells by Suppressing Negative Regulatory Mechanisms
Publisher: Elsevier BV
Date: 07-2008
Epigenetic impacts of maternal tobacco and e-vapour exposure on the offspring lung
Publisher: Springer Science and Business Media LLC
Date: 19-02-2019
Airway Smooth Muscle Hyperproliferation Is Regulated by MicroRNA-221 in Severe Asthma
Publisher: American Thoracic Society
Date: 2014
Use of biomaterials to tissue engineer 3D models with lung organoids for in-vitro disease modelling
Publisher: European Respiratory Society
Date: 07-09-2020
Transcriptional Effects of Ozone and Impact on Airway Inflammation
Publisher: Frontiers Media SA
Date: 10-07-2019
Haemophilus influenzae and Moraxella catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation
Publisher: Wiley
Date: 07-06-2023
DOI: 10.1111/ALL.15776
Abstract: Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. Whole genome sequencing was performed on induced sputum from non‐smoking (SAn) and current or ex‐smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data were analysed by asthma severity, inflammatory status and transcriptome‐associated clusters (TACs). α‐ ersity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis , and Haemophilus influenzae and Tropheryma whipplei , respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α‐ ersity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei , and Haemophilus influenzae and Moraxella catarrhalis , respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella , Neisseria and Veillonella species and Haemophilus parainfluenzae . Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack‐years of smoking. α‐ and β‐ ersities were stable at one year. Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL‐13 type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.
Correction to: Silent hypoxia: higher NO in red blood cells of COVID-19 patients
Publisher: Springer Science and Business Media LLC
Date: 10-11-2020
DOI: 10.1186/S12890-020-01326-0
Abstract: An amendment to this paper has been published and can be accessed via the original article.
Active contractility at E-cadherin junctions and its implications for cell extrusion in cancer
Publisher: Informa UK Limited
Date: 02-2015
Overcoming Steroid Insensitivity in Respiratory Disease
Publisher: Wiley
Date: 14-03-2008
Association of serum TNF-α, IL-8 and free light chain with HLA-DR B alleles expression in pulmonary and extra-pulmonary sarcoidosis
Publisher: Springer Science and Business Media LLC
Date: 19-03-2015
Prevalence and characteristics of asthma with fixed airflow obstruction:a CADSET European multi-cohort collaboration
Publisher: European Respiratory Society
Date: 05-09-2021
Corticosteroid-insensitive asthma: Molecular mechanisms
Publisher: Bioscientifica
Date: 09-2003
Abstract: Corticosteroids are the most potent anti-inflammatory agents used to treat chronic inflammatory diseases such as bronchial asthma. However, there are a small number ( %) of asthmatic patients who do not respond well, or at all, to corticosteroid therapy - the corticosteroid-resistant and corticosteroid-dependent patients. Although this phenomenon is relatively uncommon, it poses a difficult therapeutic problem because few alternative therapies are available and these patients account for % of the health care costs of asthma. If the mechanisms for corticosteroid insensitivity are understood they may, in turn, provide insight into the key mechanism of corticosteroid action and allow a rational way to treat these in iduals whose disease tends to be severe. Corticosteroid insensitivity is not limited to asthma and is a feature of other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Thus, elucidation of the cause for the relative lack of corticosteroid response in this subgroup of asthmatic in iduals may have important implications for other diseases.
Translational models of lung disease
Publisher: Portland Press Ltd.
Date: 17-10-2014
DOI: 10.1042/CS20140373
Abstract: The 2nd Cross Company Respiratory Symposium (CCRS), held in Horsham, U.K. in 2012, brought together representatives from across the pharmaceutical industry with expert academics, in the common interest of improving the design and translational predictiveness of in vivo models of respiratory disease. Organized by the respiratory representatives of the European Federation of Pharmaceutical Industries and Federations (EFPIA) group of companies involved in the EU-funded project (U-BIOPRED), the aim of the symposium was to identify state-of-the-art improvements in the utility and design of models of respiratory disease, with a view to improving their translational potential and reducing wasteful animal usage. The respiratory research and development community is responding to the challenge of improving translation in several ways: greater collaboration and open sharing of data, careful selection of the species, complexity and chronicity of the models, improved practices in preclinical research, continued refinement in models of respiratory diseases and their sub-types, greater understanding of the biology underlying human respiratory diseases and their sub-types, and finally greater use of human (and especially disease-relevant) cells, tissues and explants. The present review highlights these initiatives, combining lessons from the symposium and papers published in Clinical Science arising from the symposium, with critiques of the models currently used in the settings of asthma, idiopathic pulmonary fibrosis and COPD. The ultimate hope is that this will contribute to a more rational, efficient and sustainable development of a range of new treatments for respiratory diseases that continue to cause substantial morbidity and mortality across the world.
Effectiveness of Borage plus syrup on COVID-19 patients in intensive care units
Publisher: Frontiers Media SA
Date: 15-11-2022
Abstract: COVID-19 (coronavirus disease-2019) still causes a high rate of death globally with no definite curative treatment described. The traditional plant Borage (Borago officinalis L.) is a good source of gamma-linolenic (GLA). We hypothesized that Borage plus syrup (BPS) would be beneficial in severe COVID-19 patients within an intensive care unit (ICU) setting. A pilot single center, randomized trial with no placebo was undertaken. A total of 60 PCR-positive severe COVID-19 participants admitted to ICU from June 2020–December 2020 at Masih Daneshvari Hospital Tehran-Iran gave informed consent. The participants were randomly assigned to either Borage Plus Syrup (BPS, 5 ml for 5 days) ( n = 30) or standard care (IFN-β and favipiravir) as a control group ( n = 30). Pao2/Fio2, serum ferritin, CRP, bilirubin, IL-6, TNF-α, ALT, AST, PCT and serum IL-8 was measured upon admission and on release. All the measured parameters decreased significantly with BPS treatment. In the control group, most parameters significantly improved apart from AST and PCT. In addition, the suppression of serum TNF levels in the BPS group was greater than that seen in the control group ( P ≤ 0.05). Moreover, the length of ICU stay was significantly lower in the BPS group compared with the control group ( P ≤ 0.05). Our study shows that addition of BPS to the standard treatment regime of COVID-19 patients in ICU improved outcomes and reduced the length of ICU treatment. Natural products could be considered as new approaches for reducting the harmful consequences of COVID-19.
Eotaxin: Cloning of an Eosinophil Chemoattractant Cytokine and Increased mRNA Expression in Allergen-Challenged Guinea-Pig Lungs
Publisher: Elsevier BV
Date: 11-1994
Abstract: Eotaxin was recently identified as the major eosinophil chemoattractant in bronchoalveolar lavage fluid obtained 3h after allergen challenge of sensitised guinea-pigs. We now report the cDNA cloning of this C-C chemokine. The 777 base-pair clone, pEo3122, consists of a 40 base 5' untranslated region, an open reading frame of 288 bases predicting a 73 amino acid mature protein plus a 23 amino acid signal peptide, and a 3' untranslated region of 449 bases containing a poly A tail. Northern blot analysis showed eotaxin mRNA in the lungs of naive and sensitised guinea-pigs, which was considerably increased after allergen challenge. Eotaxin may be an important mediator of eosinophil accumulation and activation in allergic reactions. As eotaxin stimulates human eosinophils, this chemokine and related molecules may be involved in human diseases such as asthma where eosinophil accumulation is a prominent feature.
Oxidative Stress Induces NFκB DNA Binding and Inducible NOS mRNA in Human Epithelial Cells
Publisher: Elsevier BV
Date: 03-1994
Abstract: Free radicals generated by a partial reduction of O2 pose a serious threat to tissues and vital organs and cells. The major site of interaction between the lung and inhaled oxidants is the epithelium. We have examined the effect of pyrogallol, an O2- generator, on the ability of human epithelial cells to produce active DNA binding proteins and inducible nitric oxide synthase (iNOS) mRNA in cultured A549 epithelial cells. NF kappa B binding in the nuclei of these cells was determined by electrophoretic mobility shift assays. iNOS mRNA was measured using reverse transcription of PCR. There was a time- and concentration-dependent induction of NF kappa B binding, followed by a time and dose dependent increase in iNOS mRNA levels. These results suggest that in airways the initial response to oxidative stress may be to induce NF kappa B-responsive genes, such as iNOS, which may play an important role in defending the airway against oxidative stress.
Late Breaking Abstract - Comparison of the blood transcriptomic profiles of adults and children from the U-BIOPRED asthma study
Publisher: European Respiratory Society
Date: 09-2017
Predictors and associations of the persistent airflow limitation phenotype in asthma: a post-hoc analysis of the ATLANTIS study
Publisher: Elsevier BV
Date: 2023
Phospho-p38 MAPK Expression in COPD Patients and Asthmatics and in Challenged Bronchial Epithelium
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000375168
Abstract: b i Background: /i /b The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear. b i Objectives: /i /b To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli. b i Methods: /i /b Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non-smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15). Interleukin (IL)-8 and MAPK mRNA was measured in stimulated 16HBE cells. b i Results: /i /b No significant differences in p-p38 MAPK, p-JNK or p-ERK1/2 expression were seen in bronchial biopsies and peripheral airways between COPD and control subjects. Asthmatics showed increased submucosal p-p38 MAPK expression compared to COPD patients (p 0.003) and control non-smokers (p 0.05). Hydrogen peroxide (H sub /sub O sub /sub ), cytomix (tumour necrosis factor-α + IL-1β + interferon-& #947 ) and lipopolysaccharide (LPS) upregulated IL-8 mRNA at 1 or 2 h. p38 MAPKα mRNA was significantly increased after H sub /sub O sub /sub and LPS treatment. JNK1 and ERK1 mRNA were unchanged after H sub /sub O sub /sub , cytomix or LPS treatments. b i Conclusion: /i /b p-p38 MAPK expression is similar in stable COPD and control subjects but increased in the bronchi of mild asthmatics compared to stable COPD patients. p38 MAPK mRNA is increased after bronchial epithelial challenges in vitro. These data together suggest a potential role for this MAPK in Th2 inflammation and possibly during COPD exacerbations.
Combination Therapy of Long-Acting ??2-Adrenoceptor Agonists and Corticosteroids for Asthma
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.2165/00151829-200403050-00002
Abstract: Twice-daily combination therapy of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists (LABA) is now established as a most effective treatment for moderate to severe asthma and is available in a combined single inhaler. The benefits of combination therapy include better day-to-day control and a reduction in exacerbations compared with monotherapy with inhaled corticosteroids at a lower dose. Total control of asthma, defined as no daytime or night-time symptoms, no use of rescue beta2-adrenoceptor agonists (beta2-agonists), no exacerbations and a peak flow rate of >80% predicted, may be achieved with the use of combined salmeterol/fluticasone in up to 41% of patients with moderate to severe asthma, compared with only 28% of patients treated with fluticasone alone. Adjustable maintenance dosing with budesonide/formoterol may provide better control when compared with fixed-dosing combination regimens. Other therapies combining effectively with inhaled corticosteroids include slow-release theophylline and leukotriene inhibitors, montelukast and zafirlukast, but LABA are the most efficacious. Molecular interactions between corticosteroids and beta2-adrenoceptors may underlie the clinical added benefits of combination therapy. Corticosteroids may increase the number of beta2-adrenoceptors and their coupling with Gs proteins, while beta2-agonists may induce glucocorticoid receptor nuclear translocation, activate transcription factor/enhancer binding protein C/EBPalpha together with corticosteroids, or phosphorylate corticosteroid receptors. The combination of corticosteroids and LABA potentiates inhibition of interleukin-8 and eotaxin release from human airway smooth muscle cells and granulocyte-macrophage colony-stimulating factor release from epithelial cells, and also the inhibition of airway smooth muscle cell proliferation. It is important to determine whether there is a potentiating effect of combination therapy compared with corticosteroid treatment alone on airway inflammation and airway wall remodelling. Improvements in combination therapy include a once-daily preparation and possible combination of inhaled corticosteroids with newer drugs such as phosphodiesterase IV inhibitors.
The role of histone deacetylases in asthma and allergic diseases
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.JACI.2007.12.1156
Abstract: Diverse cellular functions, including inflammatory gene expression, DNA repair, and cell proliferation, are regulated by histone acetylation. Transcriptional coactivators possess intrinsic histone acetyltransferase activity, and this activity drives inflammatory gene expression and the development of tolerance in macrophages. Eleven histone deacetylases (HDACs) act to regulate the expression of distinct subsets of inflammatory/immune genes. Other proteins, particularly transcription factors, are also acetylated and are targets for deacetylation by HDACs and sirtuins, a group of protein deacetylases. HDAC inhibitors can further enhance inflammatory gene expression. However, the acetylation/deacetylation status of nonhistone proteins can also affect the overall expression pattern of inflammatory genes. HDAC2 expression and activity is reduced in lung macrophages, biopsy specimens, and blood cells from patients with severe asthma and smoking-induced asthma, as well as in patients with chronic obstructive pulmonary disease, perhaps accounting for the enhanced inflammation and reduced steroid responsiveness seen in these patients. Targeting specific enzymes involved in this process might lead to new therapeutic agents, particularly in situations in which current anti-inflammatory therapies are suboptimal.
Abstracts from The Aerosol Society Drug Delivery to the Lungs 25Edinburgh International Conference Centre Edinburgh, Scotland, UK December 10–12, 2014
Publisher: Mary Ann Liebert Inc
Date: 08-2015
Role of the mucins in pathogenesis of COPD: implications for therapy
Publisher: Informa UK Limited
Date: 19-03-2020
Pattern recognitions receptors in immunodeficiency disorders
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.EJPHAR.2017.01.014
Abstract: Pattern recognition receptors (PRRs) recognize common microbial or host-derived macromolecules and have important roles in early activation and response of the immune system. Initiation of the innate immune response starts with the recognition of microbial structures called pathogen associated molecular patterns (PAMPs). Recognition of PAMPs is performed by germline-encoded receptors expressed mainly on immune cells termed pattern recognition receptors (PRRs). Several classes of pattern recognition receptors (PRRs) are involved in the pathogenesis of diseases, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs). Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins in the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are associated with susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Altered TLR responses to TLR2 and 4 agonists are seen in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome (HIES), and for most TLRs in adenosine deaminase deficiency. In this review we provide the reader with an update on the role of TLRs and downstream signaling pathways in PID disorders.
Formoterol Attenuates Neutrophilic Airway Inflammation in Asthma
Publisher: Elsevier BV
Date: 10-2005
Abstract: Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations. Long-acting beta2-agonists (LABAs), such as formoterol, reduce the number of asthma exacerbations. While beta2-agonists may affect neutrophil function in vitro, it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo. In a double-blind randomized crossover study, we evaluated the effects of 4 weeks of treatment with formoterol (Turbuhaler), 24 microg bid, compared to placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients. Therapy with budesonide (administered via Turbuhaler), 400 microg bid for 4 weeks, was added at the end as a "gold standard" antiinflammatory effect comparison. We studied 15 steroid-naïve nonsmoking patients who ranged from 19 to 51 years of age and had mild persistent asthma. Formoterol therapy significantly reduced sputum IL-8 levels and neutrophil numbers compared to placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production. Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations.
Allergen‐induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N‐terminal kinase
Publisher: Wiley
Date: 12-2003
Glucocorticoid resistance in inflammatory diseases
Publisher: Elsevier BV
Date: 05-2009
Nasal inflammation and its response to local glucocorticoid regular treatment in patients with persistent non-allergic rhinitis: a pilot study
Publisher: Springer Science and Business Media LLC
Date: 04-08-2016
Interactions between Antarctic sea ice and large-scale atmospheric modes in CMIP5 models
Publisher: Copernicus GmbH
Date: 04-10-2016
DOI: 10.5194/TC-2016-200
Abstract: Abstract. The response of Antarctic sea ice to large-scale patterns of atmospheric variability varies according to sea ice sector and season. In this study, interannual atmosphere-sea ice interactions were explored using observation-based data and compared with simulated interactions by models in the Coupled Model Intercomparison Project Phase 5. Simulated relationships between atmospheric variability and sea ice variability generally reproduced the observed relationships, though more closely during the season of sea ice advance than the season of sea ice retreat. Atmospheric influence on sea ice is known to be strongest during its advance, with the ocean emerging as a dominant driver of sea ice retreat therefore, while it appears that models are able to capture the dominance of the atmosphere during advance, simulations of ocean-atmosphere-sea ice interactions during retreat require further investigation. A large proportion of model ensemble members overestimated the relative importance of the Southern Annular Mode compared with other modes on high southern latitude climate, while the influence of tropical forcing was underestimated. This result emerged particularly strongly during the season of sea ice retreat. The lified zonal patterns of the Southern Annular Mode in many models and its exaggerated influence on sea ice overwhelm the comparatively underestimated meridional influence, suggesting that simulated sea ice variability would become more zonally symmetric as a result. Across the seasons of sea ice advance and retreat, 3 of the 5 sectors did not reveal a strong relationship with a pattern of large-scale atmospheric variability in one or both seasons, indicating that sea ice in these sectors may be influenced more strongly by atmospheric variability unexplained by the major atmospheric modes, or by heat exchange in the ocean.
Therapeutic Potential of Phosphatidylinositol 3-Kinase Inhibitors in Inflammatory Respiratory Disease
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 04-10-2006
Abstract: The phosphoinositide 3-kinase(s) (PI3K) are a family of proteins that catalyze the phosphorylation of the 3-OH position of phosphoinositides and generate lipids that control a wide variety of intracellular signaling pathways. They are classified into three families according to their structure and substrate specificity and are thought to have distinct biological roles. Recent studies suggested that numerous components of the PI3K pathway play a crucial role in the expression and activation of inflammatory mediators, inflammatory cell recruitment, immune cell function, airway remodeling, and corticosteroid insensitivity in chronic inflammatory respiratory disease. Selective PI3K inhibitors have been developed that reduce inflammation and some characteristics of disease in experimental animal models. Targeting specific PI3K isoforms that may be overexpressed or overactive in disease should allow for selective treatment of respiratory diseases. Encouraging data from animal models, primary cells and clinical studies in other diseases suggest that inhibitors of PI3K/Akt may prove to be useful novel therapies in the treatment of asthma and chronic obstructive pulmonary disease.
S6 The profiles of JMJD3, UTX and H3K27me3 expression in pulmonary vasculature in rat MCT model of PAH and human iPAH: implications for pulmonary arterial hypertension
Publisher: BMJ
Date: 12-11-2015
Relative Corticosteroid Insensitivity of Peripheral Blood Mononuclear Cells in Severe Asthma
Publisher: American Thoracic Society
Date: 15-07-2006
In-vitroevaluation of a new potent, selective pan-Janus kinase (JAK) inhibitor VR588
Publisher: European Respiratory Society
Date: 09-2015
The lessons from U-BIOPRED
Publisher: European Respiratory Society
Date: 06-2019
Asthma and Wheeze Severity and the Oropharyngeal Microbiota in Children and Adolescents
Publisher: American Thoracic Society
Date: 12-2022
Cross‐talk between pro‐inflammatory transcription factors and glucocorticoids
Publisher: Wiley
Date: 08-2001
DOI: 10.1046/J.1440-1711.2001.01025.X
Abstract: Asthma is a chronic inflammatory disease of the airway that is characterized by cellular infiltration and activation. These processes are induced by overexpression of chemokines and cytokines, such as eotaxin, IL-1beta and GM-CSF. These mediators are downstream targets for the transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which control the expression of most immunomodulatory genes and whose activity and expression are elevated in asthma. Glucocorticoids are the most effective anti-inflammatory drugs used in the treatment of chronic inflammatory diseases such as asthma. They act by binding to a specific glucocorticoid receptor (GR) that on activation translocates to the nucleus and either increases (transactivates) or decreases (transrepresses) the expression of responsive genes. Transrepression is the major mechanism of glucocorticoid action in inhibiting inflammatory gene expression. Thus, the ability of the transcription factors AP-1 and NF-kappaB to induce gene transcription is attenuated by GR. Although only 5-10% of asthmatic subjects are glucocorticoid-insensitive, these subjects account for over 50% of the health-care costs for asthma (> $6 billion per annum). Examining these patients also gives an insight into important aspects of glucocorticoid action in controlling inflammation and into the development of potential new drugs. Biochemical and genomic studies have indicated abnormal induction of the c-Jun N-terminal kinase (JNK) pathway in some of these patients. The ability of most patients to respond to dexamethasone with induction of histone acetylation correlated with nuclear translocation of GR. However, a subgroup of these patients had an inability to correctly interact with the basal transcription complex in spite of high levels of nuclear GR. This suggests that cross-talk between pro- and anti-inflammatory transcription factors may modulate activation of the transcriptional complex and thereby reduce steroid actions.
Annexin A2 is regulated by ovarian cancer-peritoneal cell interactions and promotes metastasis
Publisher: Impact Journals, LLC
Date: 14-07-2013
Molecular mechanisms of oxidative stress in asthma
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.MAM.2021.101026
Abstract: The lungs are exposed to reactive oxygen species oxygen (ROS) produced as a result of inhalation of oxygen, as well as smoke and other air pollutants. Cell metabolism and the NADPH oxidases (Nox) generate low levels of intracellular ROS that act as signal transduction mediators by inducing oxidative modifications of histones, enzymes and transcription factors. Redox signalling is also regulated by localised production and sensing of ROS in mitochondria, the endoplasmic reticulum (ER) and inside the nucleus. Intracellular ROS are maintained at low levels through the action of a battery of enzymatic and non-enzymatic antioxidants. Asthma is a heterogeneous airway inflammatory disease with different immune endotypes these include atopic or non-atopic Th2 type immune response associated with eosinophilia, or a non-Th2 response associated with neutrophilia. Airway remodelling and hyperresponsiveness accompany the inflammatory response in asthma. Over-production of ROS resulting from infiltrating immune cells, particularly eosinophils and neutrophils, and a concomitant impairment of antioxidant responses lead to development of oxidative stress in asthma. Oxidative stress is augmented in severe asthma and during exacerbations, as well as by air pollution and obesity, and causes oxidative damage of tissues promoting airway inflammation and hyperresponsiveness. Furthermore, deregulated Nox activity, mitochondrial dysfunction, ER stress and/or oxidative DNA damage, resulting from exposure to irritants, inflammatory mediators or obesity, may lead to redox-dependent changes in cell signalling. ROS play a central role in airway epithelium-mediated sensing, development of innate and adaptive immune responses, and airway remodelling and hyperresponsiveness. Nonetheless, antioxidant compounds have proven clinically ineffective as therapeutic agents for asthma, partly due to issues with stability and in vivo metabolism of these compounds. The compartmentalised nature of ROS production and sensing, and the role of ROS in homeostatic responses and in the action of corticosteroids and β2-adrenergic receptor agonists, adds another layer of complexity to antioxidant therapy development. Nox inhibitors and mitochondrial-targeted antioxidants are in clinical development for a number of diseases but they have not yet been investigated in asthma. A better understanding of the complex role of ROS in the pathogenesis of asthma will highlight new opportunities for more targeted and effective redox therapies.
Healthy eating index (HEI) as the predictor of asthma: Findings from NHANES
Publisher: Elsevier BV
Date: 08-2023
Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes.
Publisher: American Society for Clinical Investigation
Date: 15-12-1998
DOI: 10.1172/JCI2680
Inhaled Corticosteroids in Airways Disease
Publisher: CRC Press
Date: 27-10-2009
Positional cloning of a novel gene influencing asthma from Chromosome 2q14
Publisher: Springer Science and Business Media LLC
Date: 19-10-2003
DOI: 10.1038/NG1256
Genome-Wide Association Study of Korean Asthmatics: A Comparison With UK Asthmatics
Publisher: The Korean Academy of Asthma, Allergy and Clinical Immunology and The Korean Academy of Pediatric Al
Date: 2021
IL-17–high asthma with features of a psoriasis immunophenotype
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JACI.2019.03.027
Abstract: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood s les (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes. Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota ersity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
Hydrogen Sulfide Prevents and Partially Reverses Ozone-Induced Features of Lung Inflammation and Emphysema in Mice
Publisher: American Thoracic Society
Date: 07-2016
The role of pattern recognition receptors in lung sarcoidosis
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.EJPHAR.2017.01.020
Abstract: Sarcoidosis is a granulomatous disorder of unknown etiology. Infection, genetic factors, autoimmunity and an aberrant innate immune system have been explored as potential causes of sarcoidosis. The etiology of sarcoidosis remains unknown, and it is thought that it might be caused by an infectious agent in a genetically predisposed, susceptible host. Inflammation results from recognition of evolutionarily conserved structures of pathogens (Pathogen-associated molecular patterns, PAMPs) and/or from reaction to tissue damage associated patterns (DAMPs) through recognition by a limited number of germ line-encoded pattern recognition receptors (PRRs). Due to the similar clinical and histopathological picture of sarcoidosis and tuberculosis, Mycobacterium tuberculosis antigens such early secreted antigen (ESAT-6), heat shock proteins (Mtb-HSP), catalase-peroxidase (katG) enzyme and superoxide dismutase A peptide (sodA) have been often considered as factors in the etiopathogenesis of sarcoidosis. Potential non-TB-associated PAMPs include lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria, peptidoglycan, lipoteichoic acid, bacterial DNA, viral DNA/RNA, chitin, flagellin, leucine-rich repeats (LRR), mannans in the yeast cell wall, and microbial HSPs. Furthermore, exogenous non-organic antigens such as metals, silica, pigments with/without aluminum in tattoos, pesticides, and pollen have been evoked as potential causes of sarcoidosis. Exposure of the airways to erse infectious and non-infectious agents may be important in the pathogenesis of sarcoidosis. The current review provides and update on the role of PPRs and DAMPs in the pathogenesis of sarcoidsis.
“International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.” Kian Fan Chung, Sally E. Wenzel, Jan L. Brozek, Andrew Bush, Mario Castro, Peter J. Sterk, Ian M. Adcock, E
Publisher: European Respiratory Society (ERS)
Date: 07-2018
NF-κB and Activator Protein 1 Response Elements and the Role of Histone Modifications in IL-1β-Induced TGF-β1 Gene Transcription
Publisher: The American Association of Immunologists
Date: 2006
DOI: 10.4049/JIMMUNOL.176.1.603
Abstract: Abnormal expression of TGF-β1 is believed to play an important role in the pathogenesis of a number of chronic inflammatory and immune lung diseases, including asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. Gene activation in eukaryotes requires coordinated use of specific cell signals, chromatin modifications, and chromatin remodeling. We studied the roles of the ubiquitous inflammatory transcription factors, NF-κB and AP-1, in activation of the TGF-β1 gene and histone acetylation at the TGF-β1 promoter. IL-1β-induced TGF-β1 protein secretion and mRNA expression were prevented by actinomycin D and were attenuated by the inhibitor of κB kinase 2 inhibitor AS602868 and the JNK inhibitor SP600125, suggesting a degree of transcriptional regulation mediated by the NF-κB and AP-1 pathways. We demonstrated that IL-1β activated the p65 subunit of NF-κB and the c-Jun subunit of AP-1. Using chromatin immunoprecipitation assays, we observed a sequential recruitment of p65 and c-Jun, accompanying ordered elevation of the levels of histone H4 and H3 acetylation and recruitment of RNA polymerase II at distinct regions in the native TGF-β1 promoter. The specific NF-κB and AP-1 binding sites in the TGF-β1 promoter were confirmed by an ELISA-based binding assay, and evidence for histone hyperacetylation in TGF-β1 induction was supported by the observation that the histone deacetylase inhibitor trichostatin A enhanced basal and IL-1β-induced TGF-β1 mRNA expression. Our results suggest that IL-1β-stimulated transcription of TGF-β1 is temporally regulated by NF-κB and AP-1 and involves histone hyperacetylation at distinct promoter sites.
Dexamethasone induces apoptosis in pulmonary arterial smooth muscle cells
Publisher: Springer Science and Business Media LLC
Date: 18-09-2015
Inhibitory Effect of Hydrogen Sulfide on Ozone-Induced Airway Inflammation, Oxidative Stress, and Bronchial Hyperresponsiveness
Publisher: American Thoracic Society
Date: 2015
Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma
Publisher: BMJ
Date: 09-2008
Abstract: About 5-10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1). Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 mug/ml) and dexamethasone (10(-8) and 10(-6) M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts. The inhibition of LPS-induced interleukin (IL)1beta, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha release by dexamethasone (10(-6) M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma. Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.
Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma.
Publisher: Rockefeller University Press
Date: 12-1995
Abstract: Glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases. However, a small proportion of patients is resistant to the therapeutic effects of glucocorticoids. Pharmacokinetic and ligand binding studies suggest that the molecular abnormality in steroid resistance lies distal to nuclear translocation. We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment. This reduced DNA binding was due to a decrease in the number of receptors available rather than an alteration in affinity for DNA. To study this reduced DNA binding, we examined the ability of the nuclear translocated transcription factors activator protein 1 (AP-1), nuclear factor kappa B (NF-kappa B) and cyclic AMP response element-binding protein (CREB) to bind to their DNA-binding sites and to interact with GR in PBMC from patients with steroid-sensitive and steroid-resistant asthma. There was a significant reduction in the interaction between GR and AP-1 in these steroid-resistant patients, although interaction with other transcription factors activated in inflammation (NF-kappa B and CREB) was unaffected. An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients. There were no differences in the amount of messenger RNA detected for the components of AP-1, c-Fos and c-Jun, nor in the sequences of these messenger RNAs. These results suggest either that the ability of the GR to bind to glucocorticoid response elements and AP-1 is altered in steroid-resistant patients or that increased levels of AP-1 prevent GR DNA binding, and that this may be the molecular basis of resistance to the antiinflammatory effect of steroids in these cells.
Association Between Vitamin D Deficiencies in Sarcoidosis with Disease Activity, Course of Disease and Stages of Lung Involvements
Publisher: Centre for Evaluation in Education and Science (CEON/CEES)
Date: 04-2018
Abstract: Background: Despite negative association between 25-hydroxy vitamin D and incidence of many chronic respiratory diseases, this feature was not well studied in sarcoidosis. Current study investigated the association between 25-hydroxy vitamin D deficiency with sarcoidosis chronicity, disease activity, extra-pulmonary skin manifestations, urine calcium level and pulmonary function status in Iranian sarcoidosis patients. Results of this study along with future studies, will supply more effective programs for sarcoidosis treatment. Methods: Eighty sarcoidosis patients in two groups of insufficient serum level and sufficient serum level of 25-hydroxy vitamin D were studied. Course of sarcoidosis was defined as acute and chronic sarcoidosis. Pulmonary function test (PFT) was assessed by spirometry. Skin involvements were defined as biopsy proven skin sarcoidosis. 24-hour urine calcium level was used to specify the disease activity. Stages of lung involvements were obtained by CT-scan and chest X-ray. The statistical analyses were evaluated using Statistical Package for the Social Sciences. Results: A significant negative correlation was obtained between vitamin D deficiency in sarcoidosis patients and disease chronic course and stages two to four of lung involvements. Considering other parameters of the disease and vitamin D deficiency, no significant correlation was detected. Conclusions: In conclusion, results of the current study implies in the role of vitamin 25(OH)D deficiencies in predicting the course of chronic sarcoidosis. Furthermore, it was concluded that vitamin 25(OH)D deficiency can direct pulmonary sarcoidosis toward stage 2–4 of lung involvements.
AsthmaMap: An interactive knowledge repository for mechanisms of asthma
Publisher: Elsevier BV
Date: 03-2021
Lipopolysaccharide Treatment in Vivo Induces Widespread Tissue Expression of Inducible Nitric Oxide Synthase mRNA
Publisher: Elsevier BV
Date: 11-1993
Abstract: Nitric oxide (NO) may mediate the hypotension of septic shock, but the effect of endotoxin on inducible NO synthase (iNOS) mRNA expression remains unclear. We studied the effects of lipopolysaccharide (LPS) treatment in vivo on iNOS mRNA expression using reverse transcription and polymerase chain reaction. The iNOS mRNA was absent or negligible in any tissue studied from control rats, but was markedly increased in lung, liver, spleen, skeletal muscle and kidney from LPS-treated rats. The LPS-induced increase in iNOS mRNA was prevented by dexamethasone. Our results indicate that LPS treatment in vivo induces the expression of an iNOS mRNA via a dexamethasone-sensitive mechanism, and thus provide direct molecular evidence for the involvement of NO in septic shock.
Chronic Airway Diseases Early Stratification (CADSET): a new ERS Clinical Research Collaboration
Publisher: European Respiratory Society (ERS)
Date: 03-2019
Investigation of urine lipoarabinomannan in human immunodeficiency virus patients with or without coinfection with Tuberculosis in Iran
Publisher: Medknow
Date: 12-2016
DOI: 10.1016/J.IJMYCO.2016.11.005
Abstract: Tuberculosis (TB) remains the leading cause of AIDS-related deaths among adults in countries with resource limitations. The emergence of the Xpert MTB/RIF rapid molecular assay and its subsequent World Health Organization endorsement in 2010 transformed the TB-diagnostic landscape. Xpert provided diagnostic accuracy that was far superior to that of the sputum-smear microscopy test previously used. The detection of mycobacterial lipoarabinomannan (LAM) antigen in urine has emerged as a potential point-of-care test for TB. LAM antigen is a lipopolysaccharide present in mycobacterial cell walls which is released from metabolically active or degenerating bacterial cells and appears to be present only in people with active TB. Urine-based testing has advantages over sputum-based testing because urine is easy to collect and store and lacks the infection control risks associated with sputum collection. A previously study reported that urinary-LAM testing is a rapid, low-cost, ante-mortem diagnosis for human immunodeficiency virus (HIV)-associated TB. The objective of this study was to investigate the levels of LAM in HIV patients referred to the Mashih Daneshvari Hospital Tehran, Iran. Urine from 31 HIV patients without TB, 33 HIV patients with pulmonary TB, and eight HIV patients with extrapulmonary TB was analyzed for LAM using enzyme-linked immunosorbent assay kits (Mybiosource, San Diego, CA, USA). The plasma levels of LAM in pulmonary TB/HIV patients was 7.67±2.3ng/ml compared with 4.5±1.6ng/ml in extrapulmonary TB/HIV and 6.7±1.2ng/ml in HIV patients without TB. There was no significant difference in urine LAM levels between the three groups. Our results highlight the limitations of using urine LAM levels for differentiating HIV-associated TB patients in Iran.
Noninvasive and minimally invasive techniques for the diagnosis and management of allergic diseases
Publisher: Wiley
Date: 04-2021
DOI: 10.1111/ALL.14645
Abstract: Allergic diseases of the (upper and lower) airways, the skin and the gastrointestinal tract, are on the rise, resulting in impaired quality of life, decreased productivity, and increased healthcare costs. As allergic diseases are mostly tissue‐specific, local s ling methods for respective biomarkers offer the potential for increased sensitivity and specificity. Additionally, local s ling using noninvasive or minimally invasive methods can be cost‐effective and well tolerated, which may even be suitable for primary or home care s ling. Non‐ or minimally invasive local s ling and diagnostics may enable a more thorough endotyping, may help to avoid under‐ or overdiagnosis, and may provide the possibility to approach precision prevention, due to early diagnosis of these local diseases even before they get systemically manifested and detectable. At the same time, dried blood s les may help to facilitate minimal‐invasive primary or home care s ling for classical systemic diagnostic approaches. This EAACI position paper contains a thorough review of the various technologies in allergy diagnosis available on the market, which analytes or biomarkers are employed, and which s les or matrices can be used. Based on this assessment, EAACI position is to drive these developments to efficiently identify allergy and possibly later also viral epidemics and take advantage of comprehensive knowledge to initiate preventions and treatments.
Expression of honeybee prepromelittin as a fusion protein in Escherichia coli
Publisher: Elsevier BV
Date: 10-1991
DOI: 10.1016/1046-5928(91)90095-Z
Abstract: Strategies for the expression of precursors of eukaryotic secreted proteins as part of fused proteins in Escherichia coli have been explored. A fusion protein with beta-galactosidase at the N-terminal end and honeybee prepromelittin at the C-terminal end (beta-gal-pM) was expressed in low amounts as a cleaved polypeptide, from which the promelittin portion had been removed. Inclusion in the induction culture of 10 mM MgCl2 or 8.3% (v/v) ethanol, inhibitors of signal peptidase, gave rise to the full-length beta-gal-pM fusion protein. The results suggest that a soluble recombinant fusion protein with a signal peptide in an internal location 660 residues from the N-terminus is recognized by the E. coli translocation apparatus in the inner membrane and by leader peptidase. High-level production (about 45% of total cellular proteins) of prepromelittin was achieved when it was part of a fusion protein at the C-terminus of a truncated insoluble polypeptide from bacteriophage gene 10. This fusion protein separated into inclusion bodies in an aggregated form. In contrast, attempts to express prepromelittin by itself or at the N-terminal end of a fusion with mouse dihydrofolate reductase (pM-DHFR) proved unsuccessful.
Erratum: Role of nitric oxide in allergic inflammation and bronchial hyperresponsiveness (European Journal Pharmacology (2002) 452 (123-133) PII: S0014299902022379)
Publisher: No publisher found
Date: 2002
NK1.1+ Cells and CD8+ T Cells Mediate the Antitumor Activity of Cl-IB-MECA in a Mouse Melanoma Model
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1593/NEO.101628
Epithelium‐derived cystatin SN inhibits house dust mite protease activity in allergic asthma
Publisher: Wiley
Date: 06-11-2023
DOI: 10.1111/ALL.15739
Abstract: Allergen source‐derived proteases are a critical factor in the formation and development of asthma. The cysteine protease activity of house dust mite (HDM) disrupts the epithelial barrier function. The expression of cystatin SN (CST1) is elevated in asthma epithelium. CST1 inhibits the cysteine protease activity. We aimed to elucidate the role of epithelium‐derived CST1 in the development of asthma caused by HDM. CST1 protein levels in sputum supernatants and serum of patients with asthma and healthy volunteers were measured by ELISA. The ability of CST1 protein to suppress HDM‐induced bronchial epithelial barrier function was examined in vitro. The effects of exogenous CST1 protein on abrogating HDM‐induced epithelial barrier function and inflammation were examined in mice in vivo. CST1 protein levels were higher in sputum supernatants (142.4 ± 8.95 vs 38.87 ± 6.85 ng/mL, P 0.0001) and serum (1129 ± 73.82 vs 703.1 ± 57.02 pg/mL, P = 0.0035) in patients with asthma than in healthy subjects. The levels were significantly higher in patients with not well‐ and very poorly controlled asthma than those with well‐controlled asthma. Sputum and serum CST1 protein levels were negatively correlated with lung function in asthma. CST1 protein levels were significantly lower in the serum of HDM‐specific IgE (sIgE)‐positive asthmatics than in sIgE‐negative asthmatics. The HDM‐induced epithelial barrier function disruption was suppressed by recombinant human CST1 protein (rhCST1) in vitro and in vivo. Our data indicated that human CST1 protein suppresses asthma symptoms by protecting the asthmatic bronchial epithelial barrier through inhibiting allergenic protease activity. CST1 protein may serve as a potential biomarker for asthma control.
Further resolution of non-T2 asthma subtypes from high-throughput sputum transciptomics data in U-BIOPRED
Publisher: European Respiratory Society
Date: 15-09-2018
Novel Anti‐Inflammatory Treatments for Asthma and COPD
Publisher: Wiley
Date: 03-02-2012
Abstracts: International Society for Aerosols in Medicine e.V.20th ISAM CongressMunich Holiday Inn-City Center, Germany May 30–June 3, 2015
Publisher: Mary Ann Liebert Inc
Date: 06-2015
AsthmaMap: An expert‐driven computational representation of disease mechanisms
Publisher: Wiley
Date: 30-07-2018
DOI: 10.1111/CEA.13211
Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort
Publisher: Public Library of Science (PLoS)
Date: 21-09-2018
Stratification of asthma phenotypes by airway proteomic signatures
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JACI.2019.03.013
Abstract: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.
A Transcriptome-driven Analysis of Epithelial Brushings and Bronchial Biopsies to Define Asthma Phenotypes in U-BIOPRED
Publisher: American Thoracic Society
Date: 15-02-2017
U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.JACI.2016.08.048
Abstract: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided. We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels. Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.
Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma
Publisher: European Respiratory Society (ERS)
Date: 17-03-2020
DOI: 10.1183/13993003.01340-2019
Abstract: Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma. We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild–moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV 1 ). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV 1 /forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules alent metal transporter 1 ( DMT1 ) and transferrin receptor 1 ( TFR1 ) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1 + macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo , including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses. Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
The Estrogen-Induced miR-19 Downregulates Secretory Leucoprotease Inhibitor Expression in Monocytes
Publisher: S. Karger AG
Date: 02-07-2019
DOI: 10.1159/000500419
Abstract: Compared to females, males are more susceptible to acute viral and other respiratory tract infections that display greater severity and higher mortality. In contrast, females tend to fare worse with chronic inflammatory diseases. Circulating 17β-estradiol (E2) is a female-specific factor that may influence the progression of human lung diseases. Here we hypothesize that E2 modulates the inflammatory response of monocytes through microRNA (miRNA)-based modulation of secretory leucoprotease inhibitor (SLPI), an antiprotease with immunomodulatory effects. Monocytic cells were treated ± E2, and differentially expressed miRNAs were identified using PCR profiling. Cells were transfected with miRNA mimics or antimiRs and i SLPI /i mRNA and protein levels were quantified. Luciferase activity assay using wildtype and ΔmiR-19a/b-SLPI3′UTR reporter constructs and chromatin immunoprecipitation on E2-treated monocytes were performed. E2 downregulated SLPI and upregulated miR-19 expression in monocytes. Transfection with premiR-19b reduced SLPI mRNA and protein levels and this effect was abrogated using antimiRs against miR-19b. miR-19b directly binds the SLPI 3′UTR. The mechanism responsible for E2-mediated upregulation of miR-19 occurs via increased MIR17HG promoter activity mediated by c-MYC. Overall E2 decreases SLPI expression in human monocytic cells, via changes in miRNA expression and highlights the potential for estrogen to modulate the innate immune system.
A multi-omics approach to delineate sputum microbiome-associated asthma inflammatory phenotypes
Publisher: European Respiratory Society (ERS)
Date: 25-11-2021
Decreased neutrophil phagocytosis and killing of bacteria in COVID-19 patients
Publisher: European Respiratory Society
Date: 05-09-2021
Altered airway epithelial cell landscape in U-BIOPRED severe asthma
Publisher: European Respiratory Society
Date: 04-09-2022
The regulation of IL33 following smoking cessation
Publisher: European Respiratory Society
Date: 04-09-2022
The relationship between COPD and lung cancer
Publisher: No publisher found
Date: 2015
Decreased breath excretion of redox active iron in COPD: a protective failure?
Publisher: European Respiratory Society (ERS)
Date: 23-12-2015
Proteome fingerprints define groups with distinct clinico-pathological phenotypes in the U-BIOPRED asthma study
Publisher: European Respiratory Society
Date: 09-2016
Correction: BMP-9 Induced Endothelial Cell Tubule Formation and Inhibition of Migration Involves Smad1 Driven Endothelin-1 Production
Publisher: Public Library of Science (PLoS)
Date: 28-02-2013
DOI: 10.1371/ANNOTATION/71FB82BD-FD34-497E-A887-B1167F43570A
The Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) ERS Clinical Research Collaboration: a new dawn in asthma research
Publisher: European Respiratory Society (ERS)
Date: 11-2018
CC16: A Treatable Trait in Asthma?
Publisher: American Thoracic Society
Date: 10-2023
Histone deacetylase inhibitors induce apoptosis in human eosinophils and neutrophils
Publisher: Springer Science and Business Media LLC
Date: 2010
Strategies for improving the efficacy and therapeutic ratio of glucocorticoids
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.COPH.2012.02.006
Abstract: Although glucocorticoids are very effective in suppressing inflammation there is a clear clinical unmet need for new or improved glucocorticoids in patients with severe asthma and COPD. Recent developments include the targeted deposition of ultrafine glucocorticoid particles to treat small airways and the potential of novel agents that have a reduced side effect profile. Understanding the drivers of relative glucocorticoid resistance in these patients may lead to the development of newer drugs aimed at subsets of patients, for ex le asthmatics with high periostin levels. Alternatively, inhibitors of kinase pathways that are associated with inflammatory responses may be able to modulate glucocorticoid function and combinations of these inhibitors along with novel glucocorticoids may provide the combination therapy of the future.
Precision medicine for the discovery of treatable mechanisms in severe asthma
Publisher: Wiley
Date: 15-04-2019
DOI: 10.1111/ALL.13771
Abstract: Although the complex disease of asthma has been defined as being heterogeneous, the extent of its endophenotypes remains unclear. The pharmacological approach to initiating treatment has, until recently, been based on disease control and severity. The introduction of antibody therapies targeting the Type 2 inflammation pathway for patients with severe asthma has resulted in the recognition of an allergic and an eosinophilic phenotype, which are not mutually exclusive. Concomitantly, molecular phenotyping based on a transcriptomic analysis of bronchial epithelial and sputum cells has identified a Type 2 high inflammation cluster characterized by eosinophilia and recurrent exacerbations, as well as Type 2 low clusters linked with IL-6 trans-signalling, interferon pathways, inflammasome activation and mitochondrial oxidative phosphorylation pathways. Systems biology approaches are establishing the links between these pathways or mechanisms, and clinical and physiologic features. Validation of these pathways contributes to defining endotypes and treatable mechanisms. Precision medicine approaches are necessary to link treatable mechanisms with treatable traits and biomarkers derived from clinical, physiologic and inflammatory features of clinical phenotypes. The deep molecular phenotyping of airway s les along with noninvasive biomarkers linked to bioinformatic and machine learning techniques will enable the rapid detection of molecular mechanisms that transgresses beyond the concept of treatable traits.
Extracellular Superoxide Dismutase 3 is required to efficiently clear Streptococcus pneumonia in the lung
Publisher: Wiley
Date: 23-03-2016
Correction to: Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma
Publisher: Springer Science and Business Media LLC
Date: 08-02-2021
DOI: 10.1186/S12931-021-01642-X
Abstract: An amendment to this paper has been published and can be accessed via the original article.
Expression of platelet-activating factor receptor mRNA in human and guinea pig lung.
Publisher: American Thoracic Society
Date: 05-1994
DOI: 10.1165/AJRCMB.10.5.8179916
Abstract: Platelet-activating factor (PAF) has been implicated in the pathogenesis of several inflammatory pulmonary diseases, and specific binding sites have been demonstrated in human and guinea pig lung membranes by radioligand binding experiments. Both human and guinea pig PAF receptors (PAFR) have recently been cloned. We have used molecular probes to study the gene expression of PAFR in human and animal lung and in situ hybridization to determine the distribution of PAFR mRNA in peripheral lung. Northern blot analysis of total lung RNA from human lung parenchyma, using a 1.1-kb SmaI-EcoRI fragment of human PAFR cDNA or a 0.9-kb SmaI-SmaI fragment of guinea pig PAFR cDNA, demonstrated the expression of PAFR mRNA in human lung, with a single transcript of 4 kb. There was a significant increase in PAFR mRNA in the lungs of asthmatic patients and a significant decrease in PAFR mRNA in the lungs of cigarette smokers compared with normal patients. Similarly, the expression of PAFR mRNA on guinea pig and rat lung was detected as a single transcript of 3 kb, using both guinea pig and human PAFR cDNA probes. A full-length 1.8-kb human leukocyte PAFR cDNA probe was used as the DNA template for producing 35S-labeled antisense and sense cRNA probes for use in in situ hybridization studies of human peripheral lung. These studies revealed high levels of PAFR mRNA hybridization in blood vessels, moderate levels of hybridization in alveolar walls and peripheral airway smooth muscle, but no specific signal in airway epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of N-Acetylcysteine in Ozone-Induced Chronic Obstructive Pulmonary Disease Model
Publisher: Public Library of Science (PLoS)
Date: 18-11-2013
T CELL RECEPTOR REPERTOIRE IN PERIPHERAL BLOOD AND BRONCHIAL BIOPSIES FROM NORMAL AND ASTHMATIC SUBJECTS
Publisher: Portland Press Ltd.
Date: 05-1996
DOI: 10.1042/BST024316S
Genetic differences according to onset age and lung function in asthma: A cluster analysis
Publisher: Wiley
Date: 07-2023
DOI: 10.1002/CLT2.12282
Abstract: The extent of differences between genetic risks associated with various asthma subtypes is still unknown. To better understand the heterogeneity of asthma, we employed an unsupervised method to identify genetic variants specifically associated with asthma subtypes. Our goal was to gain insight into the genetic basis of asthma. In this study, we utilized the UK Biobank dataset to select asthma patients (All asthma, n = 50,517) and controls ( n = 283,410). We excluded 14,431 in iduals who had no information on predicted values of forced expiratory volume in one second percent (FEV1%) and onset age, resulting in a final total of 36,086 asthma cases. We conducted k‐means clustering based on asthma onset age and predicted FEV1% using these s les ( n = 36,086). Cluster‐specific genome‐wide association studies were then performed, and heritability was estimated via linkage disequilibrium score regression. To further investigate the pathophysiology, we conducted eQTL analysis with GTEx and gene‐set enrichment analysis with FUMA. Clustering resulted in four distinct clusters: early onset asthma normalLF (early onset with normal lung function, n = 8172), early onset asthma reducedLF (early onset with reduced lung function, n = 8925), late‐onset asthma normalLF (late‐onset with normal lung function, n = 12,481), and late‐onset asthma reducedLF (late‐onset with reduced lung function, n = 6508). Our GWASs in four clusters and in All asthma s le identified 5 novel loci, 14 novel signals, and 51 cluster‐specific signals. Among clusters, early onset asthma normalLF and late‐onset asthma reducedLF were the least correlated ( r g = 0.37). Early onset asthma reducedLF showed the highest heritability explained by common variants ( h 2 = 0.212) and was associated with the largest number of variants (71 single nucleotide polymorphisms). Further, the pathway analysis conducted through eQTL and gene‐set enrichment analysis showed that the worsening of symptoms in early onset asthma correlated with lymphocyte activation, pathogen recognition, cytokine receptor activation, and lymphocyte differentiation. Our findings suggest that early onset asthma reducedLF was the most genetically predisposed cluster, and that asthma clusters with reduced lung function were genetically distinct from clusters with normal lung function. Our study revealed the genetic variation between clusters that were segmented based on onset age and lung function, providing an important clue for the genetic mechanism of asthma heterogeneity.
Pharmacogenomics and targeted therapy of cancer: Focusing on non-small cell lung cancer
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.EJPHAR.2015.02.029
Abstract: Recent studies have been established high degree of genetic ersity in solid organ tumors among in iduals and even between in idual tumor cells. This intratumor and intertumor genetic ersity results in a heterogeneous tumor with unique characteristics which potentially allows effective drug therapy. The goal of pharmacogenomics is to elucidate the genetic network(s) that underlie drug efficacy and drug resistance. Advances in targeted and personalized therapy play an increasingly important role in many common cancers, notably lung cancer, due to the high incidence, prevalence, mortality and the greater tendency towards drug resistance seen in these patients. Non-small cell lung cancer (NSCLC) is characterized by mutations in the epidermal growth factor receptor (EGFR) and or downstream kinase pathways. This has led to the development of highly selective monoclonal antibodies and EGFR tyrosine kinase inhibitors (EGFR-TKIs) to prevent cancer initiation, proliferation, differentiation, angiogenesis, survival, and invasion. However, resistance to many of these new treatments is induced and further pharmacogenomic analysis has revealed mutations associated with increased or reduced drug efficacy. Combinations of kinase inhibitors or potentially the targeting of cancer stem cells may further increase the success of pharmacogenomics in treating patients with lung cancer.
The Developmental Origins of Asthma
Publisher: American Thoracic Society
Date: 15-10-2009
Effect of cigarette smoking on haem-oxygenase expression in alveolar macrophages
Publisher: Elsevier BV
Date: 06-2004
DOI: 10.1016/J.RMED.2003.11.007
Abstract: We investigated the effect of chronic cigarette smoking on the expression of haem-oxygenase (HO)-1 and HO-2. Normal subjects and asymptomatic young current smokers with normal lung function tests underwent bronchoalveolar lavage for recovery of macrophages. Reverse transcription olymerase chain reaction (RT-PCR) analysis showed no significant difference in HO-1 and HO-2 mRNA expression between the two groups. On the other hand, Western blot analysis showed a significant (P<0.05) reduction of HO-2 protein, but not of HO-1, in alveolar macrophages from smokers compared to normal. There was no significant differences by immunocytochemistry for HO-1 and HO-2 expression between the groups. We concluded that HO-2 expression is reduced in alveolar macrophages of smokers, possibly due to the oxidative stress of cigarette smoke. This may in turn lead to reduced protection against further oxidative insults.
Asthmatic patients
Publisher: European Respiratory Society
Date: 2021
A Genome Wide Association Study of Moderate-Severe Asthma in subjects from the United Kingdom
Publisher: European Respiratory Society
Date: 09-2017
Impact of theophylline/corticosteroid combination therapy on sputum hydrogen sulfide levels in patients with COPD
Publisher: European Respiratory Society (ERS)
Date: 13-02-2014
Con: Genome-Wide Association Studies Have Not Been Useful in Understanding Asthma
Publisher: American Thoracic Society
Date: 15-09-2011
Extracellular matrix degradation pathways and fatty acid metabolism regulate distinct pulmonary vascular cell types in pulmonary arterial hypertension
Publisher: Wiley
Date: 2021
Abstract: Pulmonary arterial hypertension describes a group of diseases characterised by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre‐capillary resistance arterioles. Left untreated, patients die from right heart failure. Pulmonary vascular remodelling involves all cell types but to date the precise roles of the different cells is unknown. This study investigated differences in basal gene expression between pulmonary arterial hypertension and controls using both human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells. Human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells from pulmonary arterial hypertension patients and controls were cultured to confluence, harvested and RNA extracted. Whole genome sequencing was performed and after transcript quantification and normalisation, we examined differentially expressed genes and applied gene set enrichment analysis to the differentially expressed genes to identify putative activated pathways. Human pulmonary microvascular endothelial cells displayed 1008 significant ( p ≤ 0.0001) differentially expressed genes in pulmonary arterial hypertension s les compared to controls. In human pulmonary artery smooth muscle cells, there were 229 significant ( p ≤ 0.0001) differentially expressed genes between pulmonary arterial hypertension and controls. Pathway analysis revealed distinctive differences: human pulmonary microvascular endothelial cells display down‐regulation of extracellular matrix organisation, collagen formation and biosynthesis, focal‐ and cell‐adhesion molecules suggesting severe endothelial barrier dysfunction and vascular permeability in pulmonary arterial hypertension pathogenesis. In contrast, pathways in human pulmonary artery smooth muscle cells were mainly up‐regulated, including those for fatty acid metabolism, biosynthesis of unsaturated fatty acids, cell–cell and adherens junction interactions suggesting a more energy‐driven proliferative phenotype. This suggests that the two cell types play different mechanistic roles in pulmonary arterial hypertension pathogenesis and further studies are required to fully elucidate the role each plays and the interactions between these cell types in vascular remodelling in disease progression.
Chronic lung inflammation and pulmonary fibrosis after multiple intranasal instillation of PM2 .5 in mice
Publisher: Wiley
Date: 29-03-2021
DOI: 10.1002/TOX.23140
Abstract: Fine particulate matter (PM 2.5 ) is an important component of air pollution and can induce lung inflammation and oxidative stress. We hypothesized that PM 2.5 could play a role in the induction of pulmonary fibrosis. We examined whether multiple intranasal instillation of PM 2.5 can induce pulmonary fibrosis in the mouse, and also investigated the underlying pro‐fibrotic signaling pathways. C57/BL6 mice were intranasally instilled with 50 μl of PM 2.5 suspension (7.8 μg/g body weight) or PBS three times a week over 3 weeks, 6 weeks or 9 weeks. To observe the recovery of pulmonary fibrosis after the termination of PM 2.5 exposure, 9 week‐PM 2.5 instilled mice were also studied at 3 weeks after termination of instillation. There were significant decreases in total lung capacity (TLC) and compliance (Cchord) in the 9‐week PM 2.5 ‐instilled mice, while there were increased histological fibrosis scores with enhanced type I collagen and hydroxyproline deposition, increased mitochondrial ROS levels and NOX activity, decreased total SOD and GSH levels, accompanied by decreased mitochondrial number and aberrant mitochondrial morphology (swelling, vacuolization, cristal disruption, reduced matrix density) in PM 2.5 ‐instilled mice. Multiple PM 2.5 instillation resulted in increased expression of TGFβ1, increases of N‐Cadherin and Vimentin and a decrease of E‐Cadherin. It also led to decreases in OPA1 and MFN2, and increases in Parkin, SQSTM1 62, the ratio of light china (LC) 3B II to LC3B I, PI3k/Akt phosphorylation, and NLRP3 expression. Intranasal instillation of PM 2.5 for 9 weeks induced lung inflammation and pulmonary fibrosis, which was linked with aberrant epithelial‐mesenchymal transition, oxidative stress, mitochondrial damage and mitophagy, as well as activation of TGFβ1‐PI3K/Akt, TGFβ1‐ NOX and TGFβ1‐NLRP3 pathways.
Active Air Monitoring for Understanding the Ventilation and Infection Risks of SARS-CoV-2 Transmission in Public Indoor Spaces
Publisher: MDPI AG
Date: 08-12-2022
Abstract: Indoor, airborne, transmission of SARS-CoV-2 is a key infection route. We monitored fourteen different indoor spaces in order to assess the risk of SARS-CoV-2 transmission. PM2.5 and CO2 concentrations were simultaneously monitored in order to understand aerosol exposure and ventilation conditions. Average PM2.5 concentrations were highest in the underground station (261 ± 62.8 μgm−3), followed by outpatient and emergency rooms in hospitals located near major arterial roads (38.6 ± 20.4 μgm−3), the respiratory wards, medical day units and intensive care units recorded concentrations in the range of 5.9 to 1.1 μgm−3. Mean CO2 levels across all sites did not exceed 1000 ppm, the respiratory ward (788 ± 61 ppm) and the pub (bar) (744 ± 136 ppm) due to high occupancy. The estimated air change rates implied that there is sufficient ventilation in these spaces to manage increased levels of occupancy. The infection probability in the medical day unit of hospital 3, was 1.6-times and 2.2-times higher than the emergency and outpatient waiting rooms in hospitals 4 and 5, respectively. The temperature and relative humidity recorded at most sites was below 27 °C, and 40% and, in sites with high footfall and limited air exchange, such as the hospital medical day unit, indicate a high risk of airborne SARS-CoV-2 transmission.
The Use of Inhaled Corticosteroids for Patients with COPD Who Continue to Smoke Cigarettes: An Evaluation of Current Practice
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.AMJMED.2021.09.006
Abstract: The use of inhaled corticosteroids (ICS) in combination with inhaled bronchodilators for patients with chronic obstructive pulmonary disease (COPD) is a common practice in primary care settings. However, ICS-containing therapies may be less effective in patients with COPD compared with asthma, and in in iduals with COPD who continue to smoke cigarettes. Preclinical studies suggest that inflammation in COPD is very different from in asthma. Glucocorticoid receptor functioning and other innate anti-inflammatory mechanisms are altered in cells exposed to cigarette smoke. COPD may be relatively insensitive to ICS, especially in in iduals who continue to smoke. ICS-containing therapies in patients with asthma who continue to smoke may also be less effective compared with patients who do not smoke. ICS-containing therapies may be inappropriately used in some patients with COPD, and their long-term use is associated with an increased risk for side effects, including pneumonia and bone fractures in some patients. Treatment for patients with COPD should be carefully evaluated, and anti-inflammatory/bronchodilatory strategies should be chosen based on in idual patient characteristics and recommendations in current guidelines.
Does COPD Originate from Different Cell Types?
Publisher: American Thoracic Society
Date: 16-08-2023
Asthma 2 Oral Presentations
Publisher: Wiley
Date: 23-03-2016
Effects of the polyunsaturated fatty acids, EPA and DHA, on hematological malignancies: a systematic review
Publisher: Impact Journals, LLC
Date: 05-02-2018
TSANZ Ann Woolcock Young Investigator Awards Oral Presentations
Publisher: Wiley
Date: 23-03-2016
Signalling and transcriptional regulation in inflammatory and immune cells: importance in lung biology and disease
Publisher: European Respiratory Society (ERS)
Date: 11-2005
HISTONE DEACETYLASE ACTIVITY IS REDUCED IN COPD SUBJECTS DURING RHINOVIRUS INDUCED EXACERBATIONS
Publisher: BMJ
Date: 12-2011
Trends in prevalence, mortality, and disability-adjusted life-years relating to chronic obstructive pulmonary disease in Europe: an observational study of the global burden of disease database, 2001–2
Publisher: Springer Science and Business Media LLC
Date: 28-07-2022
DOI: 10.1186/S12890-022-02074-Z
Abstract: Chronic Obstructive Pulmonary Disease (COPD) is associated with significant mortality and well-defined aetiological factors. Previous reports indicate that mortality from COPD is falling worldwide. This study aims to assess the burden of COPD using prevalence, mortality, and disability-adjusted life years (DALYs) between 2001 and 2019 in 28 European countries (the European Union and the United Kingdom). We extracted COPD data from the Global Burden of Disease database based on the International Classification of Diseases versions 10 (J41, 42, 43, 44 and 47). Age-standardised prevalence rates (ASPRs), age-standardised mortality rates (ASMRs), and DALYs were analysed for European countries by sex for each year (2001–2019) and reported per 100,000 population. We used Joinpoint regression analysis to quantify changing trends in the burden of COPD. In 2019, the median ASPR across Europe was 3230/100,000 for males and 2202/100,000 for females. Between 2001 and 2019, the median percentage change in ASPR was − 9.7% for males and 4.3% for females. 23/28 countries demonstrated a decrease in ASPRs in males, and 11/28 demonstrated a decrease in females. The median percentage change in ASMR between 2001 and 2019 was − 27.5% for males and − 10.4% for females. 25/28 and 19/28 countries demonstrated a decrease in ASMR in males and females, respectively. In the EU between 2001 and 2019 COPD prevalence has overall increased in females but continues to decrease in males and in some countries, female prevalence now exceeds that of males. COPD mortality in the EU has decreased overall between 2001 and 2019 however, this decrease is not universal, particularly in females, and therefore remains a substantial source of amenable mortality.
Association of HLA-DR alleles with pulmonary cystic fibrosis
Publisher: European Respiratory Society
Date: 15-09-2018
Molecular evidence of Group 1 innate lymphoid cell activation in the U-BIOPRED cohort
Publisher: European Respiratory Society
Date: 09-2017
Pathophysiological Mechanisms of Asthma: Application of Cell and Molecular Biology Techniques
Publisher: Springer Science and Business Media LLC
Date: 2001
DOI: 10.1385/MB:18:3:213
Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease
Publisher: Elsevier BV
Date: 09-2015
Molecular Mechanisms of Glucocorticoid Receptor Action
Publisher: Wiley
Date: 14-03-2008
Correction to: Research Cigarette Smoke Exposure Alters mSin3a and Mi-2α/β Expression; implications in the control of pro-inflammatory gene transcription and glucocorticoid function
Publisher: Springer Science and Business Media LLC
Date: 23-04-2021
Dissociated Glucocorticoids
Publisher: Wiley
Date: 14-03-2008
Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids
Publisher: European Respiratory Society (ERS)
Date: 17-08-2023
DOI: 10.1183/23120541.00269-2023
Abstract: Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. To measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure. Urine collected at baseline in the U-BIOPRED study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study. The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulphate (DHEA-S) concentrations were % of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high dose ICS only, were more suppressed in females than males (p-value .05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p-value .05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12–18 months. The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.
New drugs for asthma
Publisher: Elsevier BV
Date: 09-1998
Eicosanoid mediator expression in mononuclear and polymorphonuclear cells in normal subjects and patients with atopic asthma and cystic fibrosis.
Publisher: BMJ
Date: 12-1996
Abstract: Eicosanoids such as leukotrienes, prostaglandins, lipoxins, and 15-hydroperoxyeicosatetraenoic acid (15-HETE) cause bronchoconstriction, increased microvascular permeability, mucus secretion, and polymorph chemotaxis. These pro-inflammatory effects are important in diseases such as asthma and cystic fibrosis where the levels of mediators are increased both in the stable and acute state. A study was conducted to examine the expression of the mRNA for the enzymes of the eicosanoid pathways (5-lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP), cyclo-oxygenases 1 and 2 (COX-1, COX-2), and 15-lipoxygenase (15-LO)) in normal subjects and in patients with stable atopic asthma and stable cystic fibrosis. Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the expression of total RNA for 5-LO, FLAP, COX-1, COX-2, and 15-LO in peripheral blood polymorphonuclear cells and mononuclear cells from the three subjects groups. The expression of mRNA for 5-LO and FLAP was similar in normal subjects and in patients with asthma and cystic fibrosis. COX-1 was increased in both cell types in asthmatic patients. COX-2 and 15-LO were increased in polymorphs of patients with atopic asthma but not in mononuclear cells. COX-2 and 15-LO were undetectable in either cell type in patients with cystic fibrosis whereas COX-1 levels in polymorphs were similar to those in patients with asthma. The increased leukotriene production in asthma and cystic fibrosis is not explained by an increase in transcription of 5-LO and FLAP. Transcription of 15-LO and COX-2 is increased in atopic asthma. Transcription of COX-1 is increased in both atopic asthma and cystic fibrosis.
LSC Abstract – Rhinovirus infection induces NRF2 in monocytes but not in epithelial cells, via distinct intracellular pathways
Publisher: European Respiratory Society
Date: 09-2015
An overview of methods of fine and ultrafine particle collection for physicochemical characterisation and toxicity assessments
Publisher: Elsevier BV
Date: 02-2021
Increased Serum Levels of Soluble TNF-α Receptor Is Associated With ICU Mortality in COVID-19 Patients
Publisher: Frontiers Media SA
Date: 22-04-2021
DOI: 10.3389/FIMMU.2021.592727
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected over 112M patients and resulted in almost 2.5M deaths worldwide. The major clinical feature of severe COVID-19 patients requiring ventilation is acute respiratory distress syndrome (ARDS) possibly associated with a cytokine storm. To elucidate serum levels of TNF-α and soluble TNF-Receptor 1 (sTNFR1) in patients with severe and mild COVID-19 disease as determinants of disease severity. We determined serum TNF-α and sTNFR1 concentrations in 46 patients with laboratory-confirmed COVID-19 (17 patients with severe disease within the intensive care unit [ICU] and 29 non-severe, non-ICU patients) and 15 healthy controls upon admission using ELISA. Subjects were recruited between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran. Serum levels of sTNFRI were significantly higher in ICU patients (P& .0001) and non-ICU patients (P=0.0342) compared with healthy subjects. Serum sTNFR1 were significantly higher in ICU patients than in non-ICU patients (P& .0001). Serum TNF-α levels were greater in ICU and non-ICU patients than in the healthy subjects group (p& .0001). The sTNFRI concentration in ICU (r=0.79, p=0.0002) and non-ICU (r=0.42, p=0.02) patients positively correlated with age although serum sTNFRI levels in ICU patients were significantly higher than in older healthy subjects. The sTNFRI concentration in ICU patients negatively correlated with ESR. The study demonstrates higher sTNFRI in ICU patients with severe COVID-19 disease and this be a biomarker of disease severity and mortality. Future studies should examine whether lower levels of systemic sTNFR1 at admission may indicate a better disease outcome.
Mitochondrial reactive oxygen species and glycolysis in airway smooth muscle cell proliferation in COPD
Publisher: European Respiratory Society
Date: 09-2015
Microarray analysis of long non-coding RNAs in COPD lung tissue
Publisher: Springer Science and Business Media LLC
Date: 27-12-2014
DOI: 10.1007/S00011-014-0790-9
Abstract: Long noncoding RNAs (lncRNAs) play an important role in the pathogenesis of many human diseases. In this study, we provide the description of genome-wide lncRNA expression in the lung tissue of non-smokers without Chronic obstructive pulmonary disease (COPD), of smokers without COPD and of smokers with COPD. RNA was extracted from human lung tissue and analysed using an Agilent Human lncRNA + mRNA Array v2.0 system. 39,253 distinct lncRNA transcripts were detected in the lung tissues of all subjects. In smokers without COPD 87 lncRNAs were significantly up-regulated and 244 down-regulated compared to non-smokers without COPD with RNA50010|UCSC-9199-1005 and RNA58351| CombinedLit_316_550, the most over- and under-regulated, respectively. In contrast, in COPD patients 120 lncRNAs were over-expressed and 43 under-expressed compared with smokers without COPD with RNA44121|UCSC-2000-3182 and RNA43510|UCSC-1260-3754 being the most over- and under-regulated, respectively. Gene Ontology (GO) and pathway analysis indicated that cigarette smoking was associated with activation of metabolic pathways, whereas COPD transcripts were associated with 'hematopoietic cell lineage', intermediary metabolism and immune system processes. We conclude that the altered expression of lncRNAs might play partial role in pathways implicated in COPD onset and progression such as intermediary metabolism and the immune response.
Interactions of signal and transit peptides with membrane proteins and phospholipids
Publisher: Portland Press Ltd.
Date: 10-1989
DOI: 10.1042/BST0170823
Abstract: The reniform nematode, Rotylenchulus reniformis Linford &Oliveira, has become a serious threat to cotton (Gossypium hirsutum L.) production in the United States during the past decade. The objective of this study is to isolate fungi from eggs of R. reniformis and select potential biological control agents for R. reniformis on cotton. Soil s les were collected from cotton fields located in Jefferson County, Arkansas. Eight genera of fungi were included in the 128 fungal isolates obtained, and among them were five strains of the nematophagous fungus ARF. The mtDNA RFLP pattern, colony growth characteristics, and pathogenicity indicate the five ARF isolates represent one described strain and one new strain. Light and electron microscopic observations suggest ARF is an active parasite of R. reniformis, with parasitism ranging from 48% to 79% in in vitro tests. Three greenhouse experiments demonstrated ARF successfully suppressed the number of reniform nematodes during the first and second generation of the nematode. Reductions in numbers of R. reniformis on the roots for the seven application rates of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% ARF were 87%, 92%, 94%, 96%, 97%, 98%, and and 98%, respectively.
Effects of glucocorticoids on transcription factor activation in human peripheral blood mononuclear cells
Publisher: American Physiological Society
Date: 02-1995
DOI: 10.1152/AJPCELL.1995.268.2.C331
Abstract: Glucocorticoids have an inhibitory effect on inflammatory and immune responses, and this may be through the modulation of transcription factor binding to DNA. The interaction of the transcription factors, activator protein-1 (AP-1), nuclear factor kappa B (NF kappa B), and cAMP-responsive element binding protein (CREB) with DNA and glucocorticoid receptors (GR) was analyzed in human peripheral blood mononuclear cells by gel mobility shift assays. TNF-alpha, IL-1 beta and phorbol myristate acetate (PMA) treatment increased AP-1 and NF kappa B DNA binding by up to 200% but decreased CREB binding (38%) over a 60-min time course. Dexamethasone produced a rapid and sustained increase in glucocorticoid response element binding and a concomitant 40-50% decrease in AP-1, NF kappa B, and CREB DNA binding that was blocked by combined dexamethasone and cytokine or PMA treatment. These latter effects were due to increases in the nuclear localization of GR, not to reduced amounts of the other transcription factors. This suggests that in these cells GR within the nucleus interacts with cytokine-stimulated transcription factors by the process of cross coupling. This may be an important molecular site of steroid action.
Measures of adherence in patients with severe asthma prescribed systemic steroids in the U-BIOPRED cohort
Publisher: European Respiratory Society
Date: 15-09-2018
Stratification of asthma by lipidomic profiling of induced sputum supernatant
Publisher: Elsevier BV
Date: 07-2023
Reappearance of the thymus in old rats after orchidectomy: inhibition of regeneration by testosterone
Publisher: Bioscientifica
Date: 09-1986
Abstract: The thymus is a critically important organ during development, but atrophies progressively during the ageing process after puberty and is often considered to be unimportant in adult life. We have found that the thymus, which is grossly atrophied in 12- to 15-month-old male rats, is markedly restored in size 30 days after orchidectomy. The organ then appears normal histologically, having a well-defined cortex and medulla, is vascularized and filled with thymocytes. The regeneration of the thymus after orchidectomy was inhibited in a dose–related fashion by testosterone implants which produced serum concentrations of testosterone within the physiological range. The thymus was also increased in size after orchidectomy of 10-week-old rats, and testosterone inhibited the enlargement of the thymus. These results have important implications for the possible enhancement of the immune system with associated improvement of health during ageing and disease. They also point to an important physiological link between the endocrine and immune systems. J. Endocr. (1986) 110, 417–422
CYTOKINE mRNA PROFILES OF NORMAL AND ASTHMATIC PERIPHERAL BLOOD CELLS AND ENDOBRONCHIAL BIOPSIES
Publisher: Portland Press Ltd.
Date: 05-1996
DOI: 10.1042/BST024315S
Erratum to “The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats” [Biochem. Biophys. Acta 1762 (2006) 525–532]
Publisher: Elsevier BV
Date: 08-2006
LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signalling
Publisher: Springer Science and Business Media LLC
Date: 12-01-2012
Abstract: COPD is a disease of innate immunity and bacterial infections are a dominant cause of exacerbations in the later stages resulting in poor health and high mortality. The pathogen-associated molecular pattern (PAMP) lipopolysaccharide (LPS) is sensed by immune cells through activation of the toll-like receptor 4 (TLR4). This leads to the activation of NADPH oxidase (NOX) and NF-κB which together drive COPD inflammation. In this study we show in human PBMCs that LPS stimulated proinflammatory cytokine release (CXCL8 and IL6) was inhibited by approximately 50% by the broad specificity phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Our results also demonstrate that activation of PI3K following LPS stimulation is mediated by a NOX4 dependent mechanism releasing endogenous H 2 O 2 , as the NOX4 inhibitor apocynin blocked LPS induced AKT phosphorylation. Moreover, LPS-induced PI3K activation was inhibited by the anti-oxidant N-acetylcysteine in a concentration dependent manner (IC 50 ~100 μM). In addition, our data demonstrated that inhibition of small G proteins, by pre-treatment with pertussis toxin, inhibited LPS-induced AKT phosphorylation. Furthermore, the G-protein inhibitors pertussis toxin and mastoparan both inhibited LPS-induced CXCL8 and IL-6 release by approximately 50%. Together, these data indicate there is a mechanism in human PBMCs where TLR4 activation by LPS leads to ROS generation through NOX4 and activation of the PI3K pathway. This effect is apparently mediated through small G proteins facilitating the release of pro-inflammatory cytokines.
STAT6 expression in T cells, alveolar macrophages and bronchial biopsies of normal and asthmatic subjects
Publisher: Springer Science and Business Media LLC
Date: 2012
Asthma is not a common cause of severe chronic respiratory failure in non-smokers: ALOT study
Publisher: PAGEPress Publications
Date: 30-06-2005
Abstract: Background. Little is known about the long-term natural history of asthma and the long-term clinical and functional consequences in non-smoking patients. From a functional point of view, non-smoking asthmatic patients may have a significantly greater decline in forced expiratory volume in one second (FEV1) compared with nonasthmatic subjects and may develop chronic irreversible (fixed) airflow limitation. This has been related to the physiological consequences of chronic airway inflammation causing airway remodeling. However these lesions are all potentially reversible and there is little radiological evidence indicating lung destruction (pulmonary emphysema), which is potentially irreversible, in non-smoking asthmatics. Severe chronic respiratory failure is the major cause of mortality in patients with severe chronic lung diseases. Domiciliary long-term oxygen therapy (LTOT) is an accepted treatment for patients with severe chronic respiratory failure. Our reasoning, therefore, was that if asthma is a cause of severe chronic respiratory failure in nonsmokers we should be able to find non-smoking asthmatics within a large population of patients on LTOT. The aim of our study (Asthma and Long-term Oxygen Therapy, “ALOT”) was to investigate the prevalence of non-smoking asthmatics in patients on LTOT in a multicentre, cross-sectional study. Methods. Between June and September 2003 we screened all subjects on long-term domiciliary oxygen therapy in three different hospitals in the North-East area of Italy (within the provinces of Ferrara and Bologna). Taken collectively, we have found one-hundred and eighty-four patients on LTOT. We have reviewed their clinical data (age, sex, smoking, history and physical examination, arterial blood gas analysis, pulmonary function). Results. 114 patients (all smokers) fulfilled the diagnostic criteria for COPD. Seventy patients (all smokers) had other diseases. We were unable to find any non-smokers in our screened population of subjects on long-term domiciliary oxygen therapy. Furthermore, there was no past history of asthma and/or acute wheezing episodes in either of the patient groups. Conclusions. This data suggests that asthma is an uncommon cause of severe chronic respiratory failure necessitating long-term domiciliary oxygen therapy in nonsmokers and supports the current consensus that asthma and COPD are different diseases with differing stages of severity and the concept that long-term avoidance of active smoking is fundamental for the prevention of severe chronic respiratory failure.
Molecular Mechanisms of Glucocorticoids
Publisher: Elsevier BV
Date: 2005
BMP-9 Induced Endothelial Cell Tubule Formation and Inhibition of Migration Involves Smad1 Driven Endothelin-1 Production
Publisher: Public Library of Science (PLoS)
Date: 27-01-2012
Toll-like receptor 2 and 4 have opposing roles in the pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease.
Publisher: American Physiological Society
Date: 12-10-2018
RNA-binding Proteins as a New Link Between COPD and Lung Cancer
Publisher: Springer International Publishing
Date: 2023
The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.BBADIS.2005.12.009
Abstract: Phosphodiesterase 4 (PDE4) has been suggested to a critical factor in the pathogenesis of inflammation by metabolizing cAMP in human leukocytes, endothelium and epithelium. The present study aimed at evaluating the PDE4 activity and expression, the relationship between the inflammation and cAMP- activity in the lungs, and potential interventions of PDE inhibitors and antiinflammatory drugs in the reduction of lung inflammation and goblet cell hyperplasia in allergic rats. The total leukocyte number and eosinophil number in bronchoalveolar lavegar fluid and infiltration of inflammatory cells in the perivascular and peribronchial spaces, structure changes and goblet cell hyperplasia in the OVA-sensitized and challenged allergic rats. A significant correlation was observed between the increases in cAMP-PDE activity and inflammation in the lung. Those OVA-induced changes were prevented by pretreatment with PDE inhibitor in a dose-related patterns and with glucocorticosteriod. We found an increase in the proportion of PDE4 and PDE4 gene expression, while a decrease in the proportion of PDE3 in the lung of the allergic rats. Incubation with different PDE inhibitors down-regulated OVA-induced cAMP hydrolysis. Our data suggest that PDE4C may play an important role in the airway inflammation, remodeling and goblet cell hyperplasia after repeated challenge of sensitized rats.
Role of autoimmunity in the pathogenesis of chronic obstructive pulmonary disease and pulmonary emphysema
Publisher: Elsevier
Date: 2022
Corticosteroids: use and insensitivity in severe asthma
Publisher: European Respiratory Society
Date: 03-2011
Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD
Publisher: Elsevier BV
Date: 2016
Attenuation of Ozone-Induced Airway Inflammation and Hyper-Responsiveness by c-Jun NH2 Terminal Kinase Inhibitor SP600125
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 25-04-2007
Abstract: Ozone has potent oxidizing properties, and exposure to ozone causes airway hyper-responsiveness (AHR) and lung inflammation. We determined the importance of c-Jun NH(2) terminal kinase (JNK), a member of the mitogen-activated protein kinase pathway, in ozone-induced AHR and inflammation. SP600125 [anthra[1,9-cd] pyrazol-6 (2H)-one], a specific JNK inhibitor (30 mg/kg) or vehicle, was administered by intraperitoneal injection before and after ozone exposure (3 ppm for 3 h). SP600125 significantly reduced total cells, and neutrophils in bronchoalveolar fluid recovered at 20 to 24 h after exposure and inhibited ozone-induced AHR. Ozone exposure induced activation of JNK in the lung as measured by the expression of phosphorylated-c-Jun, an effect abolished by SP600125. Gene-microarray analysis revealed that ozone increased the expression of over 400 genes by more than 2-fold, including interleukin-6 (IL-6), CXCL1 (keratinocyte cytokine), and CCL2 (monocyte chemoattractant protein-1). SP600125 modulated the expression of a subset of 29 ozone-induced genes IL-6 and CCL2 expression were further increased, whereas the expression of metallothionein 1, hemopexin, and mitogen-activated 3 kinase 6 was decreased in SP600125-treated ozone-exposed mice. Changes in mRNA for IL-6, CXCL1, and CCL2 were confirmed by real-time polymerase chain reaction. Ozone also decreased the expression of over 500 genes, with the most potent effect on angiopoietin-1. SP600125 modulated the expression of 15 of these genes, and in particular, SP600125 reversed ozone-induced decrease in expression of the redox-sensitive transcription factor, hypoxia-induced factor-1alpha. This study highlights an important role for JNK in response to oxidative stress through modulation of specific inflammatory and redox mediators. Inhibition of JNK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and AHR.
CCL11 as a potential diagnostic marker for asthma?
Publisher: Informa UK Limited
Date: 13-05-2014
DOI: 10.3109/02770903.2014.917659
Abstract: Asthma is an inflammatory airway disease characterized by airway eosinophilia, in which CCL11 (eotaxin) plays a crucial role. The aim of study is to determine the elevation of CCL11 levels in bronchoalveolar lavage fluid (BALF), blood, exhaled breath condensate (EBC) and sputum in asthma patients and to identify which medium yields the most significant change in CCL11 level. The databases of PubMed, Embase and Cochrane Centre Register of Controlled Trials were systematically searched from inception to September 2013. Controlled clinical trials that focused on CCL11 concentrations in asthma patients and controls, and their correlations with other asthma indicators were obtained. Data were analysed using Stata 12.0. Thirty studies were included in this investigation. CCL11 levels in blood, EBC and sputum were significantly higher in asthma patients than in healthy subjects. Sputum CCL11 concentrations were significantly elevated in unstable asthma patients versus stable asthma patients and in uncontrolled asthma patients versus partially controlled asthma patients. CCL11 levels in sputum and blood were negatively correlated with the lung function as measured by FEV1% predicted, and were positively correlated with BALF, EBC and sputum eosinophil counts. Similarly, CCL11 concentrations were positively correlated with eosinophil cationic protein in EBC, blood and sputum as well as with interleukin-5 in sputum and fractional exhaled nitric oxide in EBC. Steroid treatment had no significant effect on CCL11 levels. CCL11 is a potentially useful biomarker for the diagnosis and assessment of asthma severity and control, especially in sputum. CCL11 is crucial in eosinophil chemoattraction and activation in asthma pathogenesis. Further studies using anti-CCL11 approaches are needed to confirm a role for CCL11 in asthma pathogenesis particularly in patients with more severe disease.
Glucocorticoid suppression of nuclear factor-κB:: a role for histone modifications
Publisher: Portland Press Ltd.
Date: 02-2003
DOI: 10.1042/BST0310060
Abstract: Corticosteroids are by far the most effective treatment for chronic inflammatory diseases such as asthma. Inflammation in asthma is characterized by the increased expression of multiple inflammatory genes, including those that encode cytokines, chemokines, adhesion molecules, and inflammatory enzymes and receptors. Increased expression of inflammatory genes is regulated by pro-inflammatory transcription factors, such as nuclear factor κB (NF-κB). These bind to, and activate, co-activator molecules that then acetylate core histones resulting in elevated gene transcription. Corticosteroids reverse histone acetylation at the site of inflammatory gene transcription, either by direct binding of the activated glucocorticoid receptor to NF-κB-associated co-activators or by recruitment of histone deacetylases to the activated transcription complex. Understanding how corticosteroids work in asthma may help in designing novel corticosteroids with fewer systemic effects, as well as novel anti-inflammatory approaches.
A model of chronic inflammation and pulmonary emphysema after multiple ozone exposures in mice
Publisher: American Physiological Society
Date: 05-2011
DOI: 10.1152/AJPLUNG.00252.2010
Abstract: Oxidative stress plays a role in the pathophysiology of emphysema through the activation of tissue proteases and apoptosis. We examined the effects of ozone exposure by exposing BALB/c mice to either a single 3-h exposure or multiple exposures over 3 or 6 wk, with two 3-h exposures per week. Compared with air-exposed mice, the increase in neutrophils in bronchoalveolar lavage fluid and lung inflammation index was greatest in mice exposed for 3 and 6 wk. Lung volumes were increased in 3- and 6-wk-exposed mice but not in single-exposed. Alveolar space and mean linear intercept were increased in 6- but not 3-wk-exposed mice. Caspase-3 and apoptosis protease activating factor-1 immunoreactivity was increased in the airway and alveolar epithelium and macrophages of 3- and 6-wk-exposed mice. Interleukin-13, keratinocyte chemoattractant, caspase-3, and IFN-γ mRNA were increased in the 6-wk-exposed group, but heme oxygenase-1 (HO-1) mRNA decreased. matrix metalloproteinase-12 (MMP-12) and caspase-3 protein expression increased in lungs of 6-wk-exposed mice. Collagen area increased and epithelial area decreased in airway wall at 3- and 6-wk exposure. Exposure of mice to ozone for 6 wk induced a chronic inflammatory process, with alveolar enlargement and damage linked to epithelial apoptosis and increased protease expression.
A comprehensive analysis of oxidative stress in the ozone-induced lung inflammation mouse model
Publisher: Portland Press Ltd.
Date: 25-11-2013
DOI: 10.1042/CS20130039
Abstract: Ozone is an oxidizing environmental pollutant that contributes significantly to respiratory health. Exposure to increased levels of ozone has been associated with worsening of symptoms of patients with asthma and COPD (chronic obstructive pulmonary disease). In the present study, we investigated the acute and chronic effects of ozone exposure-induced oxidative stress-related inflammation mechanics in mouse lung. In particular, we investigated the oxidative stress-induced effects on HDAC2 (histone deacetylase 2) modification and activation of the Nrf2 (nuclear factor erythroid-related factor 2) and HIF-1α (hypoxia-inducible factor-1α) signalling pathways. Male C57BL/6 mice were exposed to ozone (3 p.p.m.) for 3 h a day, twice a week for a period of 1, 3 or 6 weeks. Control mice were exposed to normal air. After the last exposure, mice were killed for BAL (bronchoalveolar lavage) fluid and lung tissue collection. BAL total cell counts were elevated at all of the time points studied. This was associated with increased levels of chemokines and cytokines in all ozone-exposed groups, indicating the presence of a persistent inflammatory environment in the lung. Increased inflammation and Lm (mean linear intercept) scores were observed in chronic exposed mice, indicating emphysematous changes were present in lungs of chronic exposed mice. The antioxidative stress response was active (indicated by increased Nrf2 activity and protein) after 1 week of ozone exposure, but this ability was lost after 3 and 6 weeks of ozone exposure. The transcription factor HIF-1α was elevated in 3- and 6-week ozone-exposed mice and this was associated with increased gene expression levels of several HIF-1α target genes including Hdac2 (histone deacetylase 2), Vegf (vascular endothelial growth factor), Keap1 (kelch-like ECH-associated protein 1) and Mif (macrophage migration inhibitory factor). HDAC2 protein was found to be phosphorylated and carbonylated in nuclear and cytoplasm fractions, respectively, and was associated with a decrease in DNA-binding activity and protein expression of HDAC2. Decreased HDAC2 activity, most likely a direct result of protein modification, in combination with the loss of the antioxidative stress response and activation of the HIF-1α pathway, contribute to the inflammatory response and emphysema observed in ozone-exposed mice.
Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD
Publisher: BMJ
Date: 15-01-2014
Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP ‐10 and MET
Publisher: Wiley
Date: 11-02-2019
DOI: 10.1111/ALL.13727
Abstract: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.
Glucocorticoid receptor localization in normal and asthmatic lung.
Publisher: American Thoracic Society
Date: 09-1996
DOI: 10.1164/AJRCCM.154.3.8810618
Abstract: The localization and distribution of the human glucocorticoid receptor (GR) mRNA and protein was investigated in human lung obtained from transplant donors and recipients by in situ hybridization, RNA blot analysis, immunolocalization, and Western analysis. Subjects were either nonasthmatic or had mild asthma requiring only beta(2)-agonists. No difference in amount of GR mRNA was found in total RNA isolated from nonasthmatic or asthmatic donor lung. In situ hybridization showed the highest concentration of GR mRNA in the alveolar walls and vascular endothelium and smooth muscle, with lesser amounts in the airway epithelium and smooth muscle. There was no change in the level or sites of expression of GR mRNA between normal and asthmatic subjects. Immunolocalization of GR confirmed the in situ hybridization data. There was no change in the level or sites of expression of GR, in either the lung or airway, between normal and asthmatic subjects. Immunolocalization of GR in bronchial biopsies from two normal and asthmatic subjects confirmed the localization and distribution of GR. Western analysis and mobility shift assays confirmed no differences in GR levels between the two subject groups. The localization of GR mRNA and protein to specific cell types within lung and airway will make it possible to study the cellular targets of glucocorticoid therapy in inflammatory lung diseases such as asthma.
Evaluation of Myeloid-derived Suppressor Cells in the Blood of Iranian COVID-19 Patients
Publisher: Knowledge E DMCC
Date: 15-08-2022
DOI: 10.18502/IJAAI.V21I4.10294
Abstract: The cytokine storm and lymphopenia are reported in coronavirus disease 2019 (COVID-19). Myeloid-derived suppressive cells (MDSCs) exist in two different forms, granulocyte (G-MDSCs) and monocytic (M-MDSCs), that both suppress T-cell function. In COVID-19, the role of chemokines such as interleukin (IL)-8 in recruiting MDSCs is unclear. A recent report has correlated IL-8 and MDSCs with poor clinical outcomes in melanoma patients. In the current study, we evaluated the frequency of MDSCs and their correlation with serum IL-8 levels in severe COVID-19 patients from Iran. Thirty-seven severe patients (8 on ventilation, 29 without ventilation), thirteen moderate COVID-19 patients, and eight healthy subjects participated in this study between 10th April 2020 and 9th March 2021. Clinical and biochemical features, serum, and whole blood were obtained. CD14, CD15, CD11b, and HLA-DR expression on MDSCs was measured by flow cytometry. COVID-19 patients compared to healthy subjects had a greater frequency of M-MDSCs (12.7±13.3% vs 0.19±0.20%,), G-MDSCs (15.8±12.6% vs 0.35±0.40%,) and total-MDSCs (27.5±17.3% vs 0.55±0.41%,). M-MDSC (16.8±15.8% vs 5.4±4.8%,) and total-MDSC (33.3±18.5% vs 17.3±13.3%) frequency was higher in non- ventilated compared to moderate COVID-19 subjects. Serum IL-8 levels were higher in patients with COVID-19 than in normal healthy subjects (6.4±7.8 vs. 0.10±00 pg/mL). Ventilated patients (15.7±6.7 pg/mL), non-ventilated patients (5.7±2.7 pg/mL) and moderate patients (2.8±3.0 pg/mL) had significantly different levels of IL-8. A negative correlation was found between the frequency of G-MDSCs and the international normalized ratio (INR) test (r=-0.39), and between the frequency of total-MDSCs and oxygen saturation (%) (r=-0.39). COVID-19 patients with severe non-ventilated disease had the highest levels of M-MDSCs. In addition to systemic MDSCs, lung, serum IL-8, and other inflammatory biomarkers should be measured.
Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease?
Publisher: Wiley
Date: 13-04-2015
DOI: 10.1111/RESP.12542
Abstract: The primary function of the bronchial epithelium is to act as a defensive barrier aiding the maintenance of normal airway function. Bronchial epithelial cells (BEC) form the interface between the external environment and the internal milieu, making it a major target of inhaled insults. However, BEC can also serve as effectors to initiate and orchestrate immune and inflammatory responses by releasing chemokines and cytokines, which recruit and activate inflammatory cells. They also produce excess reactive oxygen species as a result of an oxidant/antioxidant imbalance that contributes to chronic pulmonary inflammation and lung tissue damage. Accumulated mucus from hyperplastic BEC obstructs the lumen of small airways, whereas impaired cell repair, squamous metaplasia and increased extracellular matrix deposition underlying the epithelium is associated with airway remodelling particularly fibrosis and thickening of the airway wall. These alterations in small airway structure lead to airflow limitation, which is critical in the clinical diagnosis of chronic obstructive pulmonary disease (COPD). In this review, we discuss the abnormal function of BEC within a disturbed immune homeostatic environment consisting of ongoing inflammation, oxidative stress and small airway obstruction. We provide an overview of recent insights into the function of the bronchial epithelium in the pathogenesis of COPD and how this may provide novel therapeutic approaches for a number of chronic lung diseases.
Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2
Publisher: Elsevier BV
Date: 11-2021
Cytokine expression in normal, atopic, and asthmatic subjects using the combination of sputum induction and the polymerase chain reaction.
Publisher: BMJ
Date: 10-1995
Abstract: The importance of cytokines in the asthmatic inflammatory response is becoming apparent. The aim of this study was to determine whether the non-invasive method of induced sputum combined with the polymerase chain reaction would allow the detection of messenger RNA (mRNA) encoding a range of cytokines on a qualitative basis. Four groups were studied comprising 10 normal subjects, six atopic, 10 mild and five moderately severe asthmatic subjects. Sputum was induced by the inhalation of nebulised 3.5% saline and total RNA extracted from the expectorated cells. Expression of cytokine message within induced sputum was examined by reverse transcription and the polymerase chain reaction (PCR) using primers specific for a range of cytokines (IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, RANTES, TNF alpha, IFN alpha, IFN gamma). Presence or absence of the signal was determined at 35 and 70 cycles of PCR by electrophoretic size fractionation on ethidium bromide stained agarose gels. Cytokine message was detectable in sputum by this method. All s les showed a positive result for actin control. Analysis of signal for the cytokines in all subjects showed that, at 70 cycles, IL-1, IL-5, IL-8, and TNF alpha were detected in more subjects than would be expected by chance. IL-5 mRNA was detected in more of the asthmatic patients (moderate 80%, mild 40%) than in the atopic subjects (33%), who in turn showed expression of this cytokine in more in iduals than nonatopic subjects (10%). The combination of sputum induction and PCR appears to be a useful, non-invasive tool to explore the chronic inflammation of asthma and possibly other lung disorders. It should enable differences between normal and asthmatic subjects to be identified for future confirmation by quantitative techniques.
Cigarette Smoke Suppresses the Surface Expression ofc-kitand FcεRI on Mast Cells
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/813091
Abstract: Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. COPD is mostly associated with cigarette smoking. Cigarette smoke contains over 4,700 chemical compounds, including free radicals and LPS (a Toll-Like Receptor 4 agonist) at concentrations which may contribute to the pathogenesis of diseases like COPD. We have previously shown that short-term exposure to cigarette smoke medium (CSM) can stimulate several inflammatory cells via TLR4 and that CSM reduces the degranulation of bone-marrow-derived mast cells (BMMCs). In the current study, the effect of CSM on mast cells maturation and function was investigated. Coculturing of BMMC with CSM during the development of bone marrow progenitor cells suppressed the granularity and the surface expression of c-kit and Fc ε RI receptors. Stimulation with IgE/antigen resulted in decreased degranulation and release of Th1 and Th2 cytokines. The effects of CSM exposure could not be mimicked by the addition of LPS to the culture medium. In conclusion, this study shows that CSM may affect mast cell development and subsequent response to allergic activation in a TLR4-independent manner.
BET proteins are associated with the induction of small airway fibrosis in COPD
Publisher: BMJ
Date: 27-01-2021
DOI: 10.1136/THORAXJNL-2020-215092
Abstract: In COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed. Determine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1). Primary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of COL15A1 and TNC . Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at COL15A1 and TNC promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed. COPD ASM show significantly higher COL15A1 and TNC expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at COL15A1 and TNC promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at COL15A1 and TNC . BET protein binding to acetylated histones is important in TGF-β1 induced expression of COL15A1 and TNC and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny.
NITRATIVE STRESS IS INCREASED IN COPD EXACERBATIONS FOLLOWING EXPERIMENTAL RHINOVIRUS INFECTION
Publisher: BMJ
Date: 12-2011
Myeloid-derived suppressor cells in the blood of Iranian COVID-19 patients
Publisher: Cold Spring Harbor Laboratory
Date: 09-07-2021
DOI: 10.1101/2021.07.07.21260141
Abstract: A cytokine storm and lymphopenia are reported in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection associated with coronavirus disease 2019 (COVID-19). Myeloid-derived suppressive cells (MDSCs) exist in two different forms, granulocyte (G-MDSCs) and monocytic (M-MDSCs) that both suppress T-cell function. Serum IL-6 and IL-8 levels seem to correlate with the number of blood MDSCs. To determine the frequency of MDSCs in severe COVID-19 patients from Iran and their correlations with serum IL-8 levels. 37 severe (8 on ventilation, 29 without ventilation) and 13 moderate COVID-19 patients together with 8 healthy subjects were enrolled at the Masih Daneshvari Hospital, Tehran-Iran between 10th April 2020-9th March 2021. Clinical and biochemical features, serum and whole blood were obtained. CD14, CD15, CD11b and HLA-DR expression on MDSCs was measured by flow cytometry. M-MDSCs (P≤0.0001) and G-MDSCs (P≤0.0001) frequency were higher in Iranian COVID-19 patients compared to healthy subjects. M-MDSC frequency was higher in non-ventilated compared to moderate COVID-19 subjects (P=0.004). Serum IL-8 levels were higher in patients with COVID-19 than in normal healthy subjects (P=0.03). IL8 level was significant difference in ventilated, non-ventilated and moderate patients (P=0.005). The frequency of G-MDSCs correlated negatively with INR (r=-0.39, P=0.02). Serum IL-8 levels did not correlate with the number of systemic MDSCs in COVID-19 patients. The highest levels of M-MDSCs were seen in the blood of severe non-ventilated patients. MDSC frequency in blood in the current study did not predict the survival and severity of COVID-19 patients.
Histone Acetylation and Histone Deacetylation
Publisher: Humana Press
Date: 2000
DOI: 10.1385/1-59259-072-1:309
Abstract: In the resting cell, DNA is tightly compacted to prevent transcription factor accessibility. During activation of the cell, this compact inaccessible DNA is made available to DNA-binding proteins, thus allowing the induction of gene transcription (1 ,2). DNA is packaged into chromatin, a highly organized and dynamic protein-DNA complex. The fundamental subunit of chromatin, the nucleosome, is composed of an octomer of four core histones, an H3/H4 tetramer and two H2A/H2B dimers, surrounded by 146 bp DNA (2,3). The packaging of DNA into nucleosomes acts as a barrier to the initiation of transcription by preventing the access of transcriptional factors, and RNA polymerase II, to their cognate recognition sequences (4). Specific lysine residues in the N-terminal tails of the core histone can be post-translationally modified by acetylation of the ε-amino group. The dynamic equilibrium of core histone acetylation is established and maintained by histone acetyltransferase (HAT) and histone deacetylase (HDAC). Several transcriptional regulators possess intrinsic HAT and HDAC activities, strongly suggesting that histone acetylation and deacetylation play a causal role in regulating transcription (5-8). There is compelling evidence that increased gene transcription is associated with an increase in histone acetylation hypoacetylation of histone is correlated with reduced transcription or gene silencing (2 ,7,8 Fig 1).
Mast cell gene signature enrichment associates with late-onset severe asthma
Publisher: European Respiratory Society
Date: 09-2016
Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra
Publisher: Elsevier BV
Date: 04-2021
The Immunopathogenesis of Neuroinvasive Lesions of SARS-CoV-2 Infection in COVID-19 Patients
Publisher: Frontiers Media SA
Date: 30-07-2021
DOI: 10.3389/FNEUR.2021.697079
Abstract: The new coronavirus disease COVID-19 was identified in December 2019. It subsequently spread across the world with over 125 M reported cases and 2.75 M deaths in 190 countries. COVID-19 causes severe respiratory distress however, recent studies have reported neurological consequences of infection by the COVID-19 virus SARS-CoV-2 even in subjects with mild infection and no initial neurological effects. It is likely that the virus uses the olfactory nerve to reach the CNS and that this transport mechanism enables virus access to areas of the brain stem that regulates respiratory rhythm and may even trigger cell death by alteration of these neuronal nuclei. In addition, the long-term neuronal effects of COVID-19 suggest a role for SARS-CoV-2 in the development or progression of neurodegerative disease as a result of inflammation and/or hypercoagulation. In this review recent findings on the mechanism(s) by which SARS-CoV-2 accesses the CNS and induces neurological dysregulation are summarized.
Cancers Related to Immunodeficiencies: Update and Perspectives
Publisher: Frontiers Media SA
Date: 20-09-2016
Building bridges for innovation in ageing: Synergies between action groups of the EIP on AHA
Publisher: Springer Science and Business Media LLC
Date: 26-09-2016
DOI: 10.1007/S12603-016-0803-1
Abstract: The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).
Respiratory Viral Infections in Exacerbation of Chronic Airway Inflammatory Diseases: Novel Mechanisms and Insights From the Upper Airway Epithelium
Publisher: Frontiers Media SA
Date: 25-02-2020
Underuse of spirometry by general practitioners for the diagnosis of COPD in Italy
Publisher: PAGEPress Publications
Date: 30-03-2005
Abstract: Background. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) underlines that spirometry is the gold standard as the most reproducible, standardised, and objective way of measuring airflow limitation in the diagnosis and assessment of Chronic Obstructive Pulmonary Disease (COPD). However, studies undertaken in different countries have suggested a widespread underuse of spirometry by general practitioners to establish the diagnosis of COPD. Precise estimates of the prevalence of physician-diagnosed COPD in Italy are not currently available. In collaboration with the Italian Academy of General practitioners (SIMG) we have investigated the degree of use of spirometry to establish the diagnosis of COPD in Italy. Methods. A standardised questionnaire has been selfadministered to a s le of 2425 Italian general practitioners (representing 5% of all the Italian doctors involved in general practice). They have been chosen to cover each of the Italian counties. Results. The prevalence of physician-diagnosed COPD was found to be approximately 4%. However, 30% of general practitioners do not use spirometry to establish the diagnosis of COPD. The main reasons given for the failure to use spirometry are (i) that spirometry is not necessary for the diagnosis of COPD or (ii) there are logistical limitations to the access of the patients to lung function laboratories. Conclusions. This data suggests that contrary to GOLD Guidelines, in Italy, as with other countries, spirometry is not always used in the diagnosis of COPD. There is a clear necessity for further education initiatives targeted to this group of physicians.
Superinduction of NF-κB by Actinomycin D and Cycloheximide in Epithelial Cells
Publisher: Elsevier BV
Date: 1996
Abstract: Epithelial cells are actively involved in inflammation and play a role in inflammatory diseases such as asthma. Numerous proinflammatory genes, expressed in the airway epithelium, are regulated by the transcription factor NF-kappa B. We show that the proinflammatory cytokines, IL-1 beta and TNF alpha, as well as a protein kinase C activator cause NF-kappa B activation in A549 epithelial cells. This observation is consistent with a major role for NF-kappa B in inflammation. We also demonstrate that IL-1 beta costimulation with a protein synthesis inhibitor, cycloheximide, or a transcription blocker, actinomycin D, results in superinduction of NF-kappa B but not the transcription factors Oct 1, AP-1, and Sp-1. We speculate that this may be due to lack of de novo synthesis of the NF-kappa B inhibitor, I kappa B alpha, and suggest that this phenomena may help explain the widely observed effect of mRNA superinduction of primary response genes in response to translational blockers.
eTRIKS IT platfroms for large-scale biomedical research
Publisher: European Respiratory Society
Date: 09-2015
The future of asthma research and development: a roadmap from the European Asthma Research and Innovation Partnership (EARIP)
Publisher: European Respiratory Society (ERS)
Date: 05-2017
Oxidative stress and mitochondrial dysfunction in a novel in vivo exacerbation model of severe asthma
Publisher: European Respiratory Society
Date: 07-09-2020
Suppression of lipopolysaccharide- and tumour necrosis factor-α-induced interleukin (IL)-8 expression by glucocorticoids involves changes in IL-8 promoter acetylation
Publisher: Oxford University Press (OUP)
Date: 17-08-2007
DOI: 10.1111/J.1365-2249.2007.03484.X
Abstract: There is accumulating evidence that the transrepressional effect of glucocorticoids in down-regulating proinflammatory gene expression might be regulated by an action on histone acetylation. To investigate this, we studied the effect of two glucocorticoids (dexamethasone and triamcinolone acetonide) on reducing lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-α-induced interleukin (IL)-8 release in a monocytic cell line and two lymphocytic cell lines (HUT-78 and Jurkat). The effect of the histone deacetylase inhibitor trichostatin A (TSA) on LPS- and TNF-α-induced IL-8 release and its repression by glucocorticoids was also examined. LPS and TNF-α induced IL-8 release in all three cell lines and this induction was inhibited by both dexamethasone and triamcinolone. Pretreatment of cells with TSA enhanced basal and LPS- and TNFα-stimulated IL-8 release in all three cell lines. TSA also attenuated the inhibitory effect of glucocorticoids on stimulated IL-8 release. Chromatin immunoprecipitation assays confirmed that LPS and TNF-α enhanced histone acetylation at the IL-8 promoter and that this was inhibited by triamcinolone in all three cell types. Changes in histone acetylation at the IL-8 are important in its regulation by proinflammatory and anti-inflammatory agents, and modulation of this activity may have therapeutic potential in inflammatory conditions.
Loss of Control of Asthma Following Inhaled Corticosteroid Withdrawal Is Associated With Increased Sputum Interleukin-8 and Neutrophils
Publisher: Elsevier BV
Date: 07-2007
Abstract: The role of neutrophils in exacerbations of asthma is poorly understood. We examined the effect of withdrawal of inhaled corticosteroids on sputum inflammatory indexes in a double-blind study in patients with moderate, stable asthma. Following a 2-week run in period, 24 subjects were randomized to receive either budesonide (400 microg bid) or placebo, and the study was continued for another 10 weeks. Loss of asthma control developed in 8 of 12 patients over the 10-week period of steroid withdrawal, whereas only 1 of 10 patients with budesonide treatment had exacerbations. Those with an exacerbation had increased sputum interleukin (IL)-8 (p < 0.0001) and increased sputum neutrophil numbers (p < 0.0001) compared to those without an exacerbation. The significant elevation in sputum IL-8 and neutrophil counts initially occurred 2 weeks prior to an exacerbation. Sputum neutrophilia correlated positively with changes in IL-8 levels (r(2) = 0.76, p = 0.01). Rapid withdrawal of inhaled corticosteroids results in an exacerbation of asthma that is preceded by an increase in sputum neutrophils and IL-8 concentrations, in contrast to an increase in eosinophils reported in previous studies in which inhaled steroids are slowly tapered.
RETRACTED ARTICLE: The anti-proliferative and anti-inflammatory response of COPD airway smooth muscle cells to hydrogen sulfide
Publisher: Springer Science and Business Media LLC
Date: 09-05-2018
DOI: 10.1186/S12931-018-0788-X
Abstract: COPD is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease caused, in part, by the aberrant function of airway smooth muscle (ASM). We have previously demonstrated that hydrogen sulfide (H 2 S) can inhibit ASM cell proliferation and CXCL8 release, from cells isolated from non-smokers. We examined the effect of H 2 S upon ASM cells from COPD patients. ASM cells were isolated from non-smokers, smokers and patients with COPD ( n = 9). Proliferation and cytokine release (IL-6 and CXCL8) of ASM was induced by FCS, and measured by bromodeoxyuridine incorporation and ELISA, respectively. Exposure of ASM to H 2 S donors inhibited FCS-induced proliferation and cytokine release, but was less effective upon COPD ASM cells compared to the non-smokers and smokers. The mRNA and protein expression of the enzymes responsible for endogenous H 2 S production (cystathionine-β-synthase [CBS] and 3-mercaptopyruvate sulphur transferase [MPST]) were inhibited by H 2 S donors. Finally, we report that exogenous H 2 S inhibited FCS-stimulated phosphorylation of ERK–1/2 and p38 mitogen activated protein kinases (MAPKs), in the non-smoker and smoker ASM cells, with little effect in COPD cells. H 2 S production provides a novel mechanism for the repression of ASM proliferation and cytokine release. The ability of COPD ASM cells to respond to H 2 S is attenuated in COPD ASM cells despite the presence of the enzymes responsible for H 2 S production.
Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview
Publisher: Wiley
Date: 08-2004
Dexamethasone and RU24858 Induce Survival and Growth Factor Receptor Bound protein 2, Leukotriene B4 Receptor 1 and Annexin-1 expression in primary Human Neutrophils
Publisher: SAGE Publications
Date: 2012
DOI: 10.4137/JCD.S9097
Abstract: Glucocorticoids are widely used anti-inflammatory medication in diseases like asthma and chronic obstructive pulmonary disease. Glucocorticoids can either activate (transactivation) or inhibit (transrepression) transcription. RU24858 was introduced as a “dissociated” glucocorticoid and it has been reported to transrepress but not to transactivate. The aim of this study was to compare the effects of RU24858 and dexamethasone in human neutrophils. RU24858 delayed spontaneous neutrophil apoptosis and further enhanced GM-CSF- induced neutrophil survival to a similar extent as dexamethasone. Like dexamethasone RU24858 also reduced CXCL8 and MIP-1α. Unexpectedly however, RU24858 increased the expression of the glucocorticoid-inducible genes BLT-1, Annexin-1 and Grb-2 in neutrophils to a similar level as seen with dexamethasone. We have shown here that dexamethasone and RU24858 both increase Grb-2, BLT1 and Annexin-1 expression and inhibit CXCL8 and MIP-1α production. This suggests that RU24858 was not able to dissociate between transactivation and transrepression in human neutrophils but enhanced neutrophil survival.
Histone Deacetylation: An Important Mechanism in Inflammatory Lung Diseases
Publisher: Informa UK Limited
Date: 2005
DOI: 10.1080/15412550500346683
Abstract: Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB. Gene expression is regulated by modifications such as acetylation of core histones through the concerted action of coactivators such as CBP (cAMP-response element binding protein (CREB)-binding protein) which have intrinsic histone acetyltransferase (HAT) activity and are able to recruit other HAT enzymes. Conversely gene repression is mediated via histone deacetylases (HDAC) and other corepressors. In biopsies from asthmatic subjects there is an increase in HAT activity and some reduction in HDAC activity. Both of these changes are partially reversed by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through a combination of a direct inhibition of HAT activity and by the recruitment of HDAC2 to the activated NF-kappaB-stimulated inflammatory gene complex. In chronic obstructive pulmonary disease (COPD), a corticosteroid insensitive disease, there is a reduction in HDAC activity and HDAC2 expression, which may account for the lified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation. This may also occur to differing degrees in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen within latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, acting through specific kinases, which may be able to reverse steroid resistance in COPD and other inflammatory lung diseases. The modulation of HAT/HDAC activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.
FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease
Publisher: BMJ
Date: 11-2020
DOI: 10.1136/BMJRESP-2020-000714
Abstract: Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels. The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort. This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p .008–0.02), all failed to reach the threshold (p .0028) to be considered highly significant following multi-comparison analysis. Metformin enhanced systemic levels of FN3K in COPD subjects independent of their high-expression or low-expression status. The data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality.
A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1038/MI.2015.111
Abstract: Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.
Glucocorticoid receptor nitration leads to enhanced anti-inflammatory effects of novel steroid ligands
Publisher: The American Association of Immunologists
Date: 15-09-2003
DOI: 10.4049/JIMMUNOL.171.6.3245
Abstract: It has recently emerged that posttranslational modification of proteins via nitration of tyrosine residues can alter their function. In this study, we describe that specific nitration of the glucocorticoid receptor (GR) by NCX-1015, a novel NO-donating prednisolone derivative (prednisolone 21-[4′-(nitrooxymethyl)benzoate), results in an enhancement of GR-mediated events. Incubation of PBMC and U937 cells with 1–10 μM NCX-1015 caused faster activation of GR as assessed by augmented 1) binding to [3H]dexamethasone, 2) dissociation from heat shock protein 90, and 3) nuclear translocation. PBMCs treated with NCX-1015 contained GR that had undergone tyrosine nitration. The chemistry facilitating the increase in steroid binding capacity observed with NCX-1015 is specific, because changing the position of the NO-donating group or ubiquitous nitration by addition of an NO donor was unable to mimic this event. In vivo treatment with NCX-1015 provoked GR nitration and faster heat shock protein 90 dissociation as assessed in peritoneal cells. Accordingly, NCX-1015, but not prednisolone or other derivatives, produced a rapid inhibition of the early neutrophil recruitment and mediator generation in a model of peritonitis. In conclusion, we report here for the first time that posttranslational modification of GR by this novel nitrosteroid is associated with its enhanced anti-inflammatory activity.
Retraction notice to Kinase inhibitors and airway inflammation [Eur. J. Pharmacol 533/1-3 (2006) 118 – 132 of Kinase inhibitors and airway inflammation]
Publisher: Elsevier BV
Date: 05-2012
Bromodomain and Extraterminal (BET) Protein Inhibition Restores Redox Balance and Inhibits Myofibroblast Activation
Publisher: Hindawi Limited
Date: 18-04-2019
DOI: 10.1155/2019/1484736
Abstract: Background and Objective . Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor- β (TGF- β ) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods . In TGF- β -stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α -smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions . Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF- β increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF- β -mediated NOX4 / SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF- β -induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.
Resolution of Inflammatory Responses: a brief introduction
Publisher: Portland Press Ltd.
Date: 20-03-2007
DOI: 10.1042/BST0350261
Abstract: Resolution of inflammatory responses is the regulatory process that prevents prolonged inflammation, thus avoiding diseases such as atherosclerosis, rheumatoid arthritis and transplant rejection. There are various different aspects to this process which are discussed briefly here and in the accompanying papers from this Focused Meeting.
Correction to: Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549)
Publisher: Springer Science and Business Media LLC
Date: 22-09-2020
DOI: 10.1186/S12890-020-01244-1
Abstract: An amendment to this paper has been published and can be accessed via the original article.
Cytokine production by bronchoalveolar lavage T lymphocytes in chronic obstructive pulmonary disease
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.JACI.2006.02.013
Abstract: T lymphocytes (predominantly CD8+ cells) have previously been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We sought to describe the profile of cytokine production by CD8+ and CD4+ cells isolated from bronchoalveolar lavage fluid. Bronchoalveolar lavage was performed in 11 patients with COPD (median FEV1, 63.3% of predicted value) and 9 healthy control subjects. CD8+ and CD4+ T cells were isolated by means of positive selection after macrophage depletion. CD8+ and CD4+ cells were activated with anti-CD3/CD28 antibodies for 60 hours before restimulation with phorbol 12-myristate 13-acetate-ionomycin and brefeldin. Three-color flow cytometry was used to simultaneously measure levels of intracellular cytokines. IL-4 was expressed by a higher percentage of stimulated CD8+ T cells (TC2) compared with CD4+ T cells (TH2) in patients with COPD (P = .01). In contrast, IFN-gamma was expressed in a significantly higher percentage of stimulated CD4+ T cells (TH1) than CD8+ T cells (TC1) in the COPD group (P = .04). TNF-alpha was expressed by almost all TC1 and TH1 cells, with virtually no expression by TC2 and TH2 cells. In addition, a small number of T cells expressing TNF-alpha alone without concomitant IFN-gamma or IL-4 expression were seen in the majority of subjects. There was a higher percentage of TC2 cells in subjects with COPD compared with that seen in the control group (P = .03). Stimulation with anti-CD3/CD28 antibodies increased the percentage of TC2 cells and decreased the percentage of TH2 cells. Our results suggest that there are increased numbers of TC2-like cytokine-expressing cells in the lungs of patients with COPD. These cells might be a source of TH2 cytokines, which might, at least in part, explain the lung eosinophilia associated with COPD exacerbations.
Differential macrophage activation in asthmatic sputum using U-BIOPRED transcriptomics
Publisher: European Respiratory Society
Date: 28-09-2019
REAPPEARANCE OF THYMUS OF AGEING RATS AFTER ORCHIDECTOMY
Publisher: Bioscientifica
Date: 09-1985
Abstract: There was no visible thymus in ageing rats of 18 months, and 7 days after orchidectomy there was still no evidence of a thymus. By 30 days after the operation, however, there was a well-defined and well developed bilobular thymus overlying the heart, although it was smaller than those observed in 10-week-old rats. Histologically, the tissue appeared normal, was well vascularized, filled with lymphocytes and several mitotic figures were also seen. When compared with sham-operated animals, blood from these animals had a significantly higher lymphocyte count. These results have important implications for the possible enhancement of the immune system with associated improvement of health during ageing.
Plasmapheresis reduces cytokine and immune cell levels in COVID-19 patients with acute respiratory distress syndrome (ARDS)
Publisher: Elsevier BV
Date: 11-2021
Role of non-coding RNAs in maintaining primary airway smooth muscle cells
Publisher: Springer Science and Business Media LLC
Date: 2014
The role of hypoxia and the circadian rhythm in sleep apnoea
Publisher: European Respiratory Society
Date: 09-2015
Does Neutrophil Phenotype Predict the Survival of Trauma Patients?
Publisher: Frontiers Media SA
Date: 06-09-2019
Interactions between long-acting β2-agonists and glucocorticoids
Publisher: Elsevier BV
Date: 09-2006
Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression
Publisher: European Respiratory Society (ERS)
Date: 05-2017
DOI: 10.1183/13993003.02006-2016
Abstract: Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD. Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12). The bronchial bacterial load of Pseudomonas aeruginosa , Haemophilus influenzae , Moraxella catarrhalis and Streptococcus pneumoniae was measured by quantitative real-time PCR. TLR4 and NOD1 expression was increased in the bronchial mucosa of patients with severe/very severe stable COPD compared with control subjects. TLR4 bronchial epithelial expression correlated positively with CD4 + and CD8 + cells and airflow obstruction. NOD1 expression correlated with CD8 + cells. The bronchial load of P. aeruginosa was directly correlated, but H. influenzae inversely correlated, with the degree of airflow obstruction. Bacterial load did not correlate with inflammatory cells. Bronchial epithelial overexpression of TLR4 and NOD1 in severe/very severe stable COPD, associated with increased bronchial inflammation and P. aeruginosa bacterial load, may play a role in the pathogenesis of COPD.
Chemokine Receptor Inhibitors as a Novel Option in Treatment of Asthma
Publisher: Bentham Science Publishers Ltd.
Date: 09-2004
Abstract: The migration of cells towards and into the site of an inflammatory insult is critical for maintenance of the inflammatory response and its resolution. This is particularly so in the case of asthma where recruitment of key effector cells may control disease severity, responsiveness to current therapies and the airway remodelling associated with the disease. Chemokine receptor antagonists have the hope of preventing inflammatory cell recruitment to the airway and perhaps as a consequence affect the resolution of airway remodelling. A number of selective antagonists directed at various CC and CXC receptors thought to be important in asthma are currently at various stages of clinical development. Results from these studies will determine whether chemokine receptor antagonists will prove beneficial in severe glucocorticoid-dependent and -resistant asthmatic subjects. Furthermore, it is possible that early treatment with these agents may prevent the disease from becoming established.
S63 Comparison of mechanisms of repair and regeneration in experimental models of acute respiratory distress syndrome
Publisher: BMJ Publishing Group Ltd and British Thoracic Society
Date: 12-2018
Precision Medicine Intervention in Severe Asthma (PRISM) study: molecular phenotyping of patients with severe asthma and response to biologics
Publisher: European Respiratory Society (ERS)
Date: 03-2023
DOI: 10.1183/23120541.00485-2022
Abstract: Severe asthma represents an important clinical unmet need despite the introduction of biologic agents. Although advanced omics technologies have aided researchers in identifying clinically relevant molecular pathways, there is a lack of an integrated omics approach in severe asthma particularly in terms of its evolution over time. The collaborative Korea–UK research project Precision Medicine Intervention in Severe Asthma (PRISM) was launched in 2020 with the aim of identifying molecular phenotypes of severe asthma by analysing multi-omics data encompassing genomics, epigenomics, transcriptomics, proteomics, metagenomics and metabolomics. PRISM is a prospective, observational, multicentre study involving patients with severe asthma attending severe asthma clinics in Korea and the UK. Data including patient demographics, inflammatory phenotype, medication, lung function and control status of asthma will be collected along with biological s les (blood, sputum, urine, nasal epithelial cells and exhaled breath condensate) for omics analyses. Follow-up evaluations will be performed at baseline, 1 month, 4–6 months and 10–12 months to assess the stability of phenotype and treatment responses for those patients who have newly begun biologic therapy. Standalone and integrated omics data will be generated from the patient s les at each visit, paired with clinical information. By analysing these data, we will identify the molecular pathways that drive lung function, asthma control status, acute exacerbations and the requirement for daily oral corticosteroids, and that are involved in the therapeutic response to biological therapy. PRISM will establish a large multi-omics dataset of severe asthma to identify potential key pathophysiological pathways of severe asthma.
Central role for phosphoinositide-3-kinase gamma/delta dependent signalling in eosinophilic pulmonary inflammation driven by innate lymphoid cells
Publisher: European Respiratory Society
Date: 09-2017
Conjugated Alpha-Alumina nanoparticle with vasoactive intestinal peptide as a Nano-drug in treatment of allergic asthma in mice
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.EJPHAR.2016.10.014
Abstract: Asthma is a chronic respiratory disease characterized by airway inflammation, bronchoconstriction, airway hyperresponsiveness and recurring attacks of impaired breathing. Vasoactive intestinal peptide (VIP) has been proposed as a novel anti-asthma drug due to its effects on airway smooth muscle relaxation, bronchodilation and vasodilation along with its immunomodulatory and anti-inflammatory properties. In the current study, we investigated the therapeutic effects of VIP when conjugated with α-alumina nanoparticle (α-AN) to prevent enzymatic degradation of VIP in the respiratory tract. VIP was conjugated with α-AN. Balb/c mice were sensitized and challenges with ovalbumin (OVA) or PBS and were ided in four groups VIP-treated, α-AN-treated, α-AN-VIP-treated and beclomethasone-treated as a positive control group. Specific and total IgE level, airway hyperresponsiveness (AHR), bronchial cytokine expression and lung histology were measured. α-AN-VIP significantly reduced the number of eosinophils (Eos), serum IgE level, Th2 cytokines and AHR. These effects of α-AN-VIP were more pronounced than that seen with beclomethasone or VIP alone (P<0.05). The current data indicate that α-AN-VIP can be considered as an effective nano-drug for the treatment of asthma.
Identification of oropharyngeal microbiome-driven asthma and wheezing clusters in children
Publisher: European Respiratory Society
Date: 04-09-2022
Decreased humoral immune response in the bronchi of rapid decliners with chronic obstructive pulmonary disease
Publisher: Springer Science and Business Media LLC
Date: 03-08-2022
DOI: 10.1186/S12931-022-02125-3
Abstract: Identification of COPD patients with a rapid decline in FEV1 is of particular interest for prognostic and therapeutic reasons. To determine the expression of markers of inflammation in COPD patients with rapid functional decline in comparison to slow or no decliners. In COPD patients monitored for at least 3 years (mean ± SD: 5.8 ± 3 years) for lung functional decline, the expression and localization of inflammatory markers was measured in bronchial biopsies of patients with no lung functional decline (FEV1% + 30 ± 43 ml/year, n = 21), slow (FEV1% ml/year, − 40 ± 19, n = 14) and rapid decline (FEV1% ml/year, − 112 ± 53, n = 15) using immunohistochemistry. ELISA test was used for polymeric immunoglobulin receptor (pIgR) quantitation “in vitro”. The expression of secretory IgA was significantly reduced in bronchial epithelium (p = 0.011) and plasma cell numbers was significantly reduced in the bronchial lamina propria (p = 0.017) of rapid decliners compared to no decliners. Bronchial inflammatory cell infiltration, CD4, CD8, CD68, CD20, NK, neutrophils, eosinophils, mast cells, pIgR, was not changed in epithelium and lamina propria of rapid decliners compared to other groups. Plasma cells/mm 2 correlated positively with scored total IgA in lamina propria of all patients. “In vitro” stimulation of 16HBE cells with LPS (10 μg/ml) and IL-8 (10 ng/ml) induced a significant increase while H 2 O 2 (100 μM) significantly decreased pIgR epithelial expression. These data show an impaired humoral immune response in rapid decliners with COPD, marked by reduced epithelial secretory IgA and plasma cell numbers in the bronchial lamina propria. These findings may help in the prognostic stratification and treatment of COPD.
Potential diagnostic value of pleural fluid cytokines levels for tuberculous pleural effusion
Publisher: Springer Science and Business Media LLC
Date: 12-01-2021
DOI: 10.1038/S41598-020-79685-1
Abstract: Patients with tuberculous pleural effusion (TPE) or malignant pleural effusions (MPE) frequently have similar pleural fluid profiles. New biomarkers for the differential diagnosis of TPE are required. We determined whether cytokine profiles in the PE of patients could aid the differential diagnosis of TPE. 30 patients with TPE, 30 patients with MPE, 14 patients with empyema (EMP) and 14 patients with parapneumonic effusion (PPE) were enrolled between Dec 2018 and 2019. The levels of interleukin (IL)-6, IL-18, IL-27, CXCL8, CCL-1 and IP-10 were determined in PE by ELISA along with measurements of adenosine deaminase (ADA). The best predictors of TPE were combined ADA.IL-27 [optimal cut-off value = 42.68 (10 3 U ng/l 2 ), sensitivity 100%, specificity 98.28%], ADA [cut off value 27.5 (IU/l), sensitivity 90%, specificity 96.5%] and IL-27 [cut-off value = 2363 (pg/ml), sensitivity 96.7%, specificity 98.3%, p ≤ 0.0001]. A high level of IL-6 [cut-off value = 3260 (pg/ml), sensitivity 100%, specificity 67.2%], CXCL8 [cut-off value = 144.5 (pg/ml), sensitivity 93.3%, specificity 58.6%], CCL1 [cut-off value = 54 (pg/ml), sensitivity 100%, specificity 70.7%] and IP-10 [cut-off value = 891.9 (pg/ml), sensitivity 83.3%, specificity 48.3%] were also predictive of TPE. High ADA.IL-27, ADA and IL-27 levels differentiate between TPE and non-TPE with improved specificity and diagnostic accuracy and may be useful clinically.
Mechanisms of Corticosteroid Resistance in Severe Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Publisher: Bentham Science Publishers Ltd.
Date: 11-2010
DOI: 10.2174/138161210793797889
Abstract: Inhaled glucocorticoids, also know as corticosteroids (ICS), revolutionized the treatment of asthma by suppressing airways inflammation and ICS therapy now forms the basis of treatment of asthma of all severities. More recently and usually in combination with a long-acting β-agonist (LABA), ICS use has been established in the treatment of chronic obstructive pulmonary disease (COPD). In asthma, ICS improves asthma control, lung function and prevents exacerbations, including hospital admissions and probably decreases mortality. Similar effects are seen in COPD but to a much lesser degree, however, an improvement in symptoms such as breathlessness and reduction in exacerbations occur particularly in more advanced disease with ICS. Chronic inflammation is a feature of both asthma and COPD, although there are differences in the site and characteristics of the inflammatory response. ICS have proven to be less effective in patients with severe asthma, smoking asthmatics and in patients with COPD. ICS act by binding to and activating specific cytosolic receptors (GR), which then translocate to the nucleus where they regulate gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. GR is able to selective repress specific inflammatory genes by differing actions on specific intracellular signalling pathways and transcription factors such as nuclear factor κB and on kinases pathways. Abnormal activation of these pathways may result in glucocorticoid resistance. Although, ICS/LABA combinations will remain the main focus of treatment of airways diseases in the near future other combinations that improve the efficacy of ICS by reducing the abnormal activation of pathways that cause glucocorticoid resistance will be developed.
COVID-19: Molecular and Cellular Response
Publisher: Frontiers Media SA
Date: 11-02-2021
DOI: 10.3389/FCIMB.2021.563085
Abstract: In late December 2019, a vtiral pneumonia with an unknown agent was reported in Wuhan, China. A novel coronavirus was identified as the causative agent. Because of the human-to-human transmission and rapid spread coronavirus disease 2019 (COVID-19) has rapidly increased to an epidemic scale and poses a severe threat to human health it has been declared a public health emergency of international concern (PHEIC) by the World Health Organization (WHO). This review aims to summarize the recent research progress of COVID-19 molecular features and immunopathogenesis to provide a reference for further research in prevention and treatment of SARS coronavirus2 (SARS-CoV-2) infection based on the knowledge from researches on SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV).
LSC Abstract – The AsthmaMap: Towards a community-driven reconstruction of asthma-relevant pathways and networks
Publisher: European Respiratory Society
Date: 09-2016
Integrated care pathways for airway diseases (AIRWAYS-ICPs)
Publisher: European Respiratory Society (ERS)
Date: 12-06-2014
DOI: 10.1183/09031936.00014614
Abstract: The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure 3) aiding risk stratification in chronic disease patients, using a common strategy 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing) 5) proposing a common simulation tool to assist physicians and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).
Update on Neutrophil Function in Severe Inflammation
Publisher: Frontiers Media SA
Date: 02-10-2018
Prediction of longitudinal inflammatory phenotypes using baseline sputum transcriptomics in UBIOPRED
Publisher: European Respiratory Society
Date: 28-09-2019
Fluticasone furoate and vilanterol for the treatment of chronic obstructive pulmonary disease
Publisher: Informa UK Limited
Date: 28-09-2017
DOI: 10.1080/17476348.2017.1386564
Abstract: Current national and international guidelines for the management of patients with stable chronic obstructive pulmonary disease (COPD) recommend the use of inhaled long-acting bronchodilators, inhaled glucocorticoids and their combinations for maintenance treatment of moderate to severe stable COPD. Areas covered: The role of fluticasone furoate (FF) and vilanterol (VI) once daily combination therapy for the regular treatment of patients with stable COPD is discussed in this review. Expert commentary: The regular treatment of moderate to severe stable COPD with once daily FF/VI combination therapy is effective, as seen in in several large placebo-controlled clinical trials involving many thousands of patients. FF/VI improved lung function, decreased respiratory symptoms and decreased the number of COPD exacerbations, including COPD-related hospitalizations. FF/VI combination therapy has also been approved for this indication in most countries. The use of this combination therapy may significantly decrease the economic costs for some National Health Services.
Clinical and transcriptomic profiles of severe asthmatics with high or low expression of the glucocorticoid receptor and importin-7.
Publisher: European Respiratory Society
Date: 15-09-2018
Cigarette smoke suppresses in vitro allergic activation of mouse mast cells
Publisher: Wiley
Date: 07-04-2009
DOI: 10.1111/J.1365-2222.2009.03209.X
Abstract: Mast cells are important effector cells in innate or acquired immunity that contribute to host defence. Excessive activation of mast cells can result in the development of allergic diseases, including atopic asthma. Mast cell activation by IgE and specific antigen induces the cells to release spasmogenic, vasoactive and pro-inflammatory mediators, which enhance airway smooth muscle contraction, vascular permeability and inflammatory cell recruitment. Recently, we have demonstrated that exposure of mast cells to cigarette smoke medium (CSM) triggered mast cells to produce chemokines. On the other hand, smoking may decrease the risk of allergic sensitization, which could be explained by a reduced IgE production or a diminished response of mast cells to activation of the IgE receptor. In this study, we investigated the effect of CSM on the allergic activation of mast cells through IgE and antigen. Primary cultured murine mast cells were exposed to CSM and activated with IgE and antigen or lipopolysaccharide (LPS). The release of granules, production of leukotrienes, chemokines and cytokines was determined in the supernatants by ELISA. The effect of CSM exposure on intracellular signalling, especially the nuclear factor (NF)-kappaB and extracellular signal-regulated kinase (Erk)1/2 pathways, was analysed by Western blotting. CSM suppressed IgE-mediated degranulation and cytokine release, but no effect was observed on leukotriene release. CSM induced phosphorylation of Erk1/2 in mast cells. In CSM-exposed mast cells, activating transcription factor (ATF)-1 was phosphorylated after stimulation with IgE/Ag. LPS-activated mast cells were not influenced by CSM. Our study suggests that exposure to cigarette smoke may lead to a reduced allergic activation of mast cells without affecting their response to activation via e.g. bacterial-derived LPS.
Retraction Note: The anti-proliferative and anti-inflammatory response of COPD airway smooth muscle cells to hydrogen sulfide
Publisher: Springer Science and Business Media LLC
Date: 25-08-2021
Activation of NF‐κB transcription factor in asthma death
Publisher: Wiley
Date: 03-2009
Corrigendum to “Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation” [European Journal of Pharmacology 600 (2008) 117-122]
Publisher: Elsevier BV
Date: 05-2009
Role of mediators in late‐phase allergic symptoms including congestion
Publisher: Wiley
Date: 17-05-2002
Bone Morphogenic Proteins and their antagonists in the lower airways of stable COPD patients
Publisher: European Respiratory Society
Date: 04-09-2022
Corticosteroid inhibition of growth-related oncogene protein-α via mitogen-activated kinase phosphatase-1 in airway smooth muscle cells
Publisher: The American Association of Immunologists
Date: 06-2007
DOI: 10.4049/JIMMUNOL.178.11.7366
Abstract: Expression of the inflammatory chemokine, growth-related oncogene protein-α (GRO-α), from airway smooth muscle cells (ASMC) is regulated by pathways involving NF-κB and MAPK activation. We determined the effects of dexamethasone on GRO-α induced by IL-1β or TNF-α with respect to the role of MAPK pathways and of MAPK phosphatase-1 (MKP-1). Human ASMC were studied in primary culture at confluence. Dexamethasone (10−8–10−5 M) partially inhibited GRO-α expression and release induced by IL-1β and TNF-α this was associated with an inhibition of JNK, but not of p38 or ERK phosphorylation. Together with IL-1β or TNF-α, dexamethasone rapidly induced mRNA and protein expression of MKP-1, which dephosphorylates MAPKs. Using MKP-1 small interfering RNA (siRNA) to block the expression of IL-1β- and dexamethasone-induced MKP-1 by 50%, JNK phosphorylation was doubled. The inhibitory effect of dexamethasone on GRO-α release was partially reversed in ASMC treated with MKP-1 siRNA compared with those treated with scrambled siRNA. In contrast, overexpression of MKP-1 led to a reduction in IL-1β-induced release of GRO-α, but the inhibitory effects of dexamethasone were preserved. Nuclear translocation of the glucocorticoid receptor was increased in ASMC exposed to dexamethasone and IL-1β. Using chromatin immunoprecipitation assay, glucocorticoid receptor binding to the MKP-1 promoter was increased by IL-1β and dexamethasone compared with either alone. Glucocorticoids and IL-1β or TNF-α modulate GRO-α release partly through the inhibition of JNK pathway, resulting from an up-regulation of MKP-1 expression.
TGFβ1 allele association with asthma severity
Publisher: Springer Science and Business Media LLC
Date: 27-10-2001
DOI: 10.1007/S00439-001-0617-Y
Abstract: Transforming growth factor beta1 (TGFbeta1) is a multifunctional cytokine involved in pro- and anti-inflammatory pathways and is expressed in several cell types. Subepithelial fibrosis is one of the principle features of airway remodelling in asthma and is increased in severe patients. TGFbeta1 is implicated in fibrosis, including the deposition of extracellular matrix proteins. TGFbeta1 mRNA levels in eosinophils are increased in severe asthmatics relative to mild asthmatics. Therefore, TGFbeta1 is a promising candidate gene for contributing to asthma severity. Four polymorphisms located in the promoter region and signal peptide (C-509T, 72insC, T869C and G915C) were genotyped in groups of severe asthmatic, mild asthmatic or control in iduals defined by steroid usage and pulmonary function. Significant differences ( P=0.016) were found between the groups for the genotype frequencies at C-509T, attributable mainly to a greater relative frequency of homozygosity for the -509T allele in the severe group compared to the mild and control groups. In iduals homozygous for -509T were also homozygous at the other variant sites for the 72C, 869C and 915G alleles (haplotype 1). The T allele creates a putative YY1 transcription factor binding site, but binding between YY1 and the DNA sequence of the T allele was not detected in vitro. In this study, we show that the -509T variant on haplotype 1 is the most informative marker of the TGFbeta1 contribution to asthma severity.
Agonist-induced up-regulation of platelet-activating factor receptor messenger RNA in human monocytes
Publisher: Elsevier BV
Date: 07-1994
DOI: 10.1016/0922-4106(94)90197-X
Abstract: Platelet-activating factor (PAF) is a potent inflammatory mediator and it actions are mediated via specific cell surface receptors which are coupled to G-proteins. PAF stimulates several functions in monocytes and may modulate the expression of its own receptor. To investigate the possible modulation of PAF receptor mRNA expression Northern blot analysis of total RNA from human monocytes was performed using the cDNA of human leukocyte PAF receptor as a probe. Following the addition of 100 nM PAF, there was a 2.0-fold increase in PAF receptor mRNA at 60 minutes after the stimulation, which was inhibited by pretreatment with the PAF receptor antagonist WEB 2086. This increase returned to control level at 120 and 180 min. The increase of PAF receptor mRNA was statistically significant for 10 nM to 1 microM of PAF, while 100 nM of lysoPAF did not increase PAF receptor mRNA levels. These results suggest that PAF receptor expression can be regulated by PAF itself at the transcriptional level.
An improved and rapid procedure for isolating RNA-Free Escherichia coli plasmid DNA
Publisher: Elsevier BV
Date: 05-1991
DOI: 10.1016/1050-3862(91)90045-S
Abstract: We describe a simple, rapid, and inexpensive procedure for the isolation of plasmid DNA in high yields from Escherichia coli cultures. The procedure entails two main steps, which involve treating intact bacterial cells with phenol/chloroform in the presence of Triton X-100 and LiCl followed by polyethylene glycol precipitation. Plasmid DNA preparations isolated by this method are highly pure and virtually devoid of RNA. The DNA is suitable substrate for restriction mapping, DNA-modifying enzymes, and in vitro transcription with SP6 and T7 RNA polymerases.
Redox Regulation of Histone Deacetylases and Glucocorticoid-Mediated Inhibition of the Inflammatory Response
Publisher: Mary Ann Liebert Inc
Date: 2005
Abstract: Gene expression, at least in part, is regulated by changes in histone acetylation status induced by activation of the proinflammatory redox-sensitive transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB). Hyperacetylated histone is associated with open actively transcribed DNA and enhanced inflammatory gene expression. In contrast, hypoacetylated histone is linked to a closed repressed DNA state and a lack of gene expression. The degree of inflammatory gene expression is a result of a balance between histone acetylation and histone deacetylation. One of the major mechanisms of glucocorticoid function is to recruit histone deacetylase enzymes to the site of active gene expression, thus reducing inflammation. Oxidative stress can enhance inflammatory gene expression by further stimulating AP-1- and NF-kappaB-mediated gene expression and elevating histone acetylation. In addition, oxidants can reduce glucocorticoid function by attenuating histone deacetylase activity and expression. Thus, oxidant stress, acting through changes in chromatin structure, can enhance inflammation and induce a state of relative glucocorticoid insensitivity. This may account for the lack of glucocorticoid sensitivity in patients with chronic obstructive pulmonary disease. Antioxidants should reduce the inflammation and restore glucocorticoid sensitivity in these subjects.
Epigenetics in asthma and other inflammatory lung diseases
Publisher: Future Medicine Ltd
Date: 08-2010
DOI: 10.2217/EPI.10.27
Abstract: Asthma is a chronic inflammatory disease of the airways. The causes of asthma and other inflammatory lung diseases are thought to be both environmental and heritable. Genetic studies do not adequately explain the heritability and susceptabilty to the disease, and recent evidence suggests that epigentic changes may underlie these processes. Epigenetics are heritable noncoding changes to DNA and can be influenced by environmental factors such as smoking and traffic pollution, which can cause genome-wide and gene-specific changes in DNA methylation. In addition, alterations in histone acetyltransferase/deacetylase activities can be observed in the cells of patients with lung diseases such as severe asthma and chronic obstructive pulmonary disease, and are often linked to smoking. Drugs such as glucocorticoids, which are used to control inflammation, are dependent on histone deacetylase activity, which may be important in patients with severe asthma and chronic obstructive pulmonary disease who do not respond well to glucocorticoid therapy. Future work targeting specific histone acetyltransferases/deacetylases or (de)methylases may prove to be effective future anti-inflammatory treatments for patients with treatment-unresponsive asthma.
The Role of HLA-DRB1 Alleles in Pulmonary Cystic Fibrosis
Publisher: Knowledge E DMCC
Date: 17-04-2022
DOI: 10.18502/IJAAI.V21I2.9226
Abstract: Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in white Caucasians. It affects many organs including the lung, pancreas, and liver. Whilst CF is a monogenic disease, several studies revealed a complex relationship between genotype and clinical phenotype of diseases. We examined the expression of human leukocyte antigen (HLA) class II alleles among Iranian CF patients with disease-related microbial infection. This study was conducted on 50 hospitalized CF patients (27 males, 23 females aged 15.5±6.5 years), and 50 healthy age- and gender-matched control subjects. 5ml whole blood was harvested and after isolation of genomic DNA, HLA-DRB1 subtypes were determined by single specific primer polymerase chain reaction methods. HLA-DRB1*10 was less frequent and HLA-DRB1*04 and HLA-DRB1*11 was the most frequent allele in CF patients, but none reached significance. HLA-DRB1*04 allele was frequently seen among16 CF patients with high serum IgE levels (430.25±219.7 IU/mL) and 27 CF patients that were positive for Pseudomonas aeruginosa colonization. A total of 31 CF patients had candida Albicans colonization in whom HLA-DRB1*11 was mostly seen. A total of 3 CF patients had allergic bronchopulmonary aspergillosis and two were diabetic. The DR4 and DR11 serotypes that recognize the HLA-DRB1*04 and HLA-DRB1*11 gene products respectively are not significantly enriched in the Iranian CF population. Further research should be conducted on DR4 and DR11 in CF patients to understand their possible role in infection and IgE expression.
<p>Bacterial load and inflammatory response in sputum of alpha-1 antitrypsin deficiency patients with COPD</p>
Publisher: Informa UK Limited
Date: 08-2019
DOI: 10.2147/COPD.S207203
S64 Clinical and transcriptomic profiles of severe asthmatics with high or low expression of the glucocorticoid receptor and importin-7
Publisher: BMJ Publishing Group Ltd and British Thoracic Society
Date: 15-11-2017
Effects of dexamethasone on cytokine and phorbol ester stimulated c-Fos and c-Jun DNA binding and gene expression in human lung
Publisher: European Respiratory Society (ERS)
Date: 12-1994
DOI: 10.1183/09031936.94.07122117
Abstract: Glucocorticosteroids have a wide variety of effects which result in the long-term d ening of inflammatory responses. An important site of steroid action may be on the control of the activator protein-1 (AP-1) binding to deoxyribonucleic acid (DNA). AP-1 is a proinflammatory transcription factor composed of a heterodimer of Fos and Jun proto-oncogenes, which can be induced by phorbol esters and various cytokines. We have examined the hypothesis that dexamethasone may inhibit inflammation via an effect on AP-1 activation in human lung tissue. The effect of dexamethasone on the phorbol ester and cytokine activation of AP-1 and its monomers was examined in human lung tissue obtained from transplantation donors. AP-1 activation was measured by its ability to bind DNA, its localization in the nucleus by Western blotting, and the levels of fos and jun messenger ribonucleic acids (mRNAs) using Northern blotting. The phorbol ester, phorbol myristate acetate (PMA), caused a significant 2-3 fold increase in AP-1 DNA binding, which was sustained for 24 h and completely attenuated by co-incubation with dexamethasone. Dexamethasone alone caused a 40% decrease in AP-1 DNA binding. Dexamethasone modulated the expression of both c-jun and c-fos mRNA and produced long-term (24 h) 40% reduction in both mRNAs when compared to control tissues. PMA induced a rapid and prolonged increase in c-Fos and c-Jun nuclear localization, which was not attenuated by co-incubation with dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)
S67 Persistent frequent exacerbators: a subtype of severe asthma
Publisher: BMJ Publishing Group Ltd and British Thoracic Society
Date: 15-11-2017
Glucocorticoids: New mechanisms and future agents
Publisher: Springer Science and Business Media LLC
Date: 05-2003
Dissociation of DNA damage and mitochondrial injury caused by hydrogen peroxide in SV-40 transformed lung epithelial cells.
Publisher: Springer Science and Business Media LLC
Date: 2002
Abstract: BACKGROUND: Since lung epithelial cells are constantly being exposed to reactive oxygen intermediates (ROIs), the alveolar surface is a major site of oxidative stress, and each cell type may respond differently to oxidative stress. We compared the extent of oxidative DNA damage with that of mitochondrial injury in lung epithelial cells at the single cell level. RESULT: DNA damage and mitochondrial injury were measured after oxidative stress in the SV-40 transformed lung epithelial cell line challenged with hydrogen peroxide (H2O2). Single cell analysis of DNA damage was determined by assessing the number of 8-oxo-2-deoxyguanosine (8-oxo-dG) positive cells, a marker of DNA modification, and the length of a comet tail. Mitochondrial membrane potential, DeltaPsim, was determined using JC-1. A 1 h pulse of H2O2 induced small amounts of apoptosis (3%). 8-oxo-dG-positive cells and the length of the comet tail increased within 1 h of exposure to H2O2. The number of cells with reduced DeltaPsim increased after the addition of H2O2 in a concentration-dependent manner. In spite of a continual loss of DeltaPsim, DNA fragmentation was reduced 2 h after exposure to H2O2. CONCLUSION: The data suggest that SV-40 transformed lung epithelial cells are resistant to oxidative stress, showing that DNA damage can be dissociated from mitochondrial injury.
Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline
Publisher: European Respiratory Society (ERS)
Date: 26-09-2019
DOI: 10.1183/13993003.00588-2019
Abstract: This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force's questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes 2) suggest using a blood eosinophil cut-point ≥150 μL −1 to guide anti-IL-5 initiation in adult patients with severe asthma 3) suggest considering specific eosinophil (≥260 μL −1 ) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy 4) suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4–5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies 5) suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.
Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.PUPT.2008.11.002
Abstract: Ambient ozone has been linked to the worsening of symptoms of patients with obstructive diseases such as chronic obstructive pulmonary disease (COPD) and asthma. We investigated the role of cathepsin S on ozone-induced airway hyperresponsiveness (AHR) and inflammation, using the selective cathepsin S inhibitor, Compound A. Balb/c mice were exposed to ozone at a concentration of 3 ppm or air for 3 h, following administration by gavage of Compound A or vehicle. Bronchoalveolar lavage (BAL) was performed 3 h and 20-24 h following exposure, AHR was measured at 20-24 h only. Ozone exposure, compared to air exposure increased BAL cathepsin S levels, AHR and BAL inflammatory cells. Compound A (30 mg kg(-1) p.o.) dosing compared to vehicle dosing inhibited ozone-induced AHR (-logPC100 vehicle: -0.70+/-0.12, n=8 vs. cathepsin S inhibitor: -1.30+/-0.06, P<0.001, n=8) at 20-24 h and BAL neutrophilia at 3 h and 20-24 h (P<0.05, n=6). Ozone exposure increased levels of BAL cytokines IL-6, TNF-alpha and IFN-gamma. Compound A reduced IL-6 at 3 h and 20-24 h (P<0.05, n=5) and TNF-alpha, at 20-24 h (P<0.05, n=6). These data indicate an important role for cathepsin S in the regulation of ozone-induced AHR and neutrophil cell recruitment and suggest that cathepsin S may be a target in the treatment of oxidative stress-induced AHR and inflammation.
Theophylline Restores Histone Deacetylase Activity and Steroid Responses in COPD Macrophages
Publisher: Rockefeller University Press
Date: 30-08-2004
DOI: 10.1084/JEM.20040416
Abstract: Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress. Histone deacetylase (HDAC) activity is reduced in cells of cigarette smokers, and low concentrations of theophylline can increase HDAC activity. We measured the effect of theophylline on HDAC activity and inflammatory gene expression in alveolar macrophages (AM) from patients with COPD. AM from normal smokers showed a decrease in HDAC activity compared with normal control subjects, and this was further reduced in COPD patients (51% decrease, P & 0.01). COPD AMs also showed increased basal release of IL-8 and TNF-α, which was poorly suppressed by dexamethasone. Theophylline induced a sixfold increase in HDAC activity in COPD AM lysates and significantly enhanced dexamethasone suppression of induced IL-8 release, an effect that was blocked by the HDAC inhibitor trichostatin A. Therefore, theophylline might restore steroid responsiveness in COPD patients.
Mechanisms and biomarkers of airway epithelial cell damage in asthma: A review
Publisher: Wiley
Date: 26-07-2021
DOI: 10.1111/CRJ.13407
Abstract: Bronchial asthma is a heterogeneous disease with complex pathological mechanisms representing different phenotypes, including severe asthma. The airway epithelium is a major site of complex pathological changes in severe asthma due, in part, to activation of inflammatory and immune mechanisms in response to noxious agents. Current imaging procedures are unable to accurately measure epithelial and airway remodeling. Damage of airway epithelial cells occurs is linked to specific phenotypes and endotypes which provides an opportunity for the identification of biomarkers reflecting epithelial, and airway, remodeling. Identification of patients with more severe epithelial disruption using biomarkers may also provide personalised therapeutic opportunities and/or markers of successful therapeutic intervention. Here, we review the evidence for ongoing epithelial cell dysregulation in the pathogenesis of asthma, the sentinel role of the airway epithelium and how understanding these molecular mechanisms provides the basis for the identification of candidate biomarkers for asthma prediction, prevention, diagnosis, treatment and monitoring.
Pathway discovery using transcriptomic profiles in adult-onset severe asthma
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.JACI.2017.06.037
Abstract: Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous s les. We sought to identify gene profiles associated with adult-onset severe asthma. This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (<18 years) were selected from the U-BIOPRED cohort. Gene expression was assessed on the total RNA of induced sputum (n = 83), nasal brushings (n = 41), and endobronchial brushings (n = 65) and biopsies (n = 47) (Affymetrix HT HG-U133+ PM). Gene set variation analysis was used to identify differentially enriched predefined gene signatures of leukocyte lineage, inflammatory and induced lung injury pathways. Significant differentially enriched gene signatures in patients with adult-onset as compared with childhood-onset severe asthma were identified in nasal brushings (5 signatures), sputum (3 signatures), and endobronchial brushings (6 signatures). Signatures associated with eosinophilic airway inflammation, mast cells, and group 3 innate lymphoid cells were more enriched in adult-onset severe asthma, whereas signatures associated with induced lung injury were less enriched in adult-onset severe asthma. Adult-onset severe asthma is characterized by inflammatory pathways involving eosinophils, mast cells, and group 3 innate lymphoid cells. These pathways could represent useful targets for the treatment of adult-onset severe asthma.
Novel targets in inflammation research ¶Report from the joint BIRAs/GREMI Meeting at Nottingham University UK on 11 th –12 th April 2002
Publisher: Springer Science and Business Media LLC
Date: 10-2002
DOI: 10.1007/PL00012415
Effects of inhaled beta agonist and corticosteroid treatment on nuclear transcription factors in bronchial mucosa in asthma
Publisher: BMJ
Date: 06-1999
DOI: 10.1136/THX.54.6.488
Abstract: Inhaled corticosteroids and beta agonists are the most commonly used treatments in asthma and are often used together. Recent evidence suggests that many of the anti-inflammatory actions of corticosteroids are mediated by cross-talk between the activated glucocorticoid receptor (GR) and other transcription factors such as the pro-inflammatory nuclear factor kappa B (NFkappaB). Beta agonists can activate the transcription factor cAMP response element binding protein (CREB). A mutual inhibition between GR and CREB occurs in vitro which raises the possibility of a negative interaction between corticosteroid and beta agonist drugs. A study was undertaken to determine whether these interactions occur during treatment with beta2 agonists and corticosteroids in asthma. Seven subjects who were participating in a randomised, placebo controlled, crossover study of six weeks treatment with inhaled budesonide (400 microg twice daily), terbutaline (1 mg four times daily), and combined treatment were recruited. Biopsy s les of the bronchial mucosa were obtained after each treatment and analysed for the DNA binding activity of GR, CREB, and NFkappaB. Budesonide increased GR activity (p<0.05) and decreased NFkappaB activity (p<0.05). No treatment combination altered CREB activity and terbutaline had no significant effects on any transcription factor. Inhaled corticosteroids have significant effects on GR and NFkappaB activity in bronchial mucosa. A negative interaction between inhaled corticosteroids and beta agonists was not found.
Subtypes of eosinophilic asthma with discrete gene pathway phenotypes
Publisher: European Respiratory Society
Date: 28-09-2019
SMADS AS INTRACELLULAR MEDIATORS OF AIRWAY INFLAMMATION
Publisher: Informa UK Limited
Date: 2004
DOI: 10.1080/01902140490276320
Abstract: Transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of allergic asthma and other airway diseases. Signals from the activated TGF-beta receptor complex are transduced to the nucleus of airway cells by Smad proteins, which represent a family of transcription factors that have recently been implicated to play a major role as intracellular mediators of inflammation. The Smad family consists of the receptor-regulated Smads, a common pathway Smad, and inhibitory Smads. Receptor-regulated Smads (R-Smads) are phosphorylated by the TGF-beta type Ireceptor. They include Smad2 and Smad3, which are recognized by TGF-beta and activin receptors, and Smads 1, 5, 8, and 9, which are recognized by bone morphogenetic protein (BMP) receptors. Smad4 is a common pathway Smad, which is also defined as cooperating Smad (co-Smad) and is not phosphorylated by the TGF-beta type I receptor. Inhibitory Smads(anti-Smads) include Smad6 and Smad7, which down-regulate TGF-beta signaling. To date, the Smads are the only TGF-beta receptor substrates with a demonstrated ability to propagate signals and with regard to the growing number of investigations of Smad-mediated effects in the airways, Smads may prove to be an important target for future development of new therapeutic strategies for asthma and chronic obstructive pulmonary disease.
Histone Acetylation and Histone Deacetylation
Publisher: Springer Science and Business Media LLC
Date: 2002
DOI: 10.1385/MB:20:1:099
Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema
Publisher: Springer Science and Business Media LLC
Date: 22-11-2018
Chronic systemic administration of salmeterol to rats promotes pulmonary β2‐adrenoceptor desensitization and down‐regulation of Gsα
Publisher: Wiley
Date: 03-2001
Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
Publisher: European Respiratory Society (ERS)
Date: 25-11-2021
DOI: 10.1183/13993003.01733-2021
Abstract: Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication. Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort 12–18-month longitudinal s les were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods. A total of 90 metabolites were identified, with 40 significantly altered (p .05, false discovery rate .05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10 −20 ), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10 −4 ), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings. This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.
Differential expression of IL‐10 receptor by epithelial cells and alveolar macrophages
Publisher: Wiley
Date: 06-04-2004
Ligand‐induced differentiation of glucocorticoid receptor (GR) trans‐repression and transactivation: preferential targetting of NF‐κB and lack of I‐κB involvement
Publisher: Wiley
Date: 06-1999
Physiology of severe vs. mild-moderate U-BIOPRED cohorts interpreted using a computational model
Publisher: European Respiratory Society
Date: 09-2015
Cigarette smoke stimulates the production of chemokines in mast cells
Publisher: Oxford University Press (OUP)
Date: 21-12-2007
DOI: 10.1189/JLB.0907625
Abstract: Chronic obstructive pulmonary disease is a major health problem and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular, cigarette smoke (CS), causes the progressive airflow limitation, in which macrophages and neutrophils are attracted by chemokines, leading to oxidative stress, emphysema, small airways fibrosis, and mucus hypersecretion. Smoking is also associated with an increase in mast cell numbers in bronchial mucosa. This study was conducted to determine the direct effects of CS on mast cell function, using murine bone marrow-derived mast cells (BMMC) as an in vitro model. BMMC were cultured from BALB/cBy mice for 3 weeks. Cells were treated with CS medium (CSM) for 30 min or 16 h. The effects of CSM on mast cell degranulation and chemokine production were measured. Moreover, we investigated the effect of CSM on IκB-α degradation and p38, Erk1/2, p65, and CREB expression by Western blotting. We found that CSM stimulated the release of chemokines in a noncytotoxic manner but did not induce mast cell degranulation. CSM induced phosphorylation of Erk1/2, p38, and CREB and increased translocation of p65 without degradation of IκB-α NF-κB in mast cells. The induction of chemokine production by CSM in mast cells could promote and prolong the inflammatory process. Our observations suggest that mast cells may contribute to the pathogenesis of emphysema through a direct effect of CS on the production of proinflammatory chemokines.
Bromodomain And Extra-Terminal (BET) proteins regulate metabolic and redox function in COPD airway smooth muscle cells
Publisher: European Respiratory Society
Date: 09-2017
Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.EJPHAR.2008.09.031
Abstract: Ozone is a potent oxidant and causes airway hyperresponsiveness and neutrophilia. To determine the role of p38 mitogen-activated protein kinase (MAPK) activation, we studied the effect of a p38alpha inhibitor SD-282 (Scios Inc, Fremont, CA USA) on ozone-induced airway hyperresponsiveness and neutrophilia. Balb/c mice received SD-282 (30 or 90 mg/kg i.p) or vehicle 1 h before exposure to either ozone (3 ppm, 3 h) or air. Three hours after exposure, lungs were analysed for cytokine levels and bronchoalveolar lavage was performed. Another set of mice were dosed 6 h after exposure and 1 h before assessing airway hyperresponsiveness. SD-282 (90 mg/kg) significantly inhibited ozone-induced airway hyperresponsiveness (-LogPC(150): SD-282: -1.73+/-0.14 vs. vehicle: -0.99+/-0.15, P<0.05). Bronchoalveolar lavage neutrophil numbers were time-dependently increased in vehicle-dosed, ozone-exposed mice, greatest at 20-24 h after exposure. SD-282 (30 and 90 mg/kg) significantly inhibited ozone induced neutrophil numbers at 3 h and 20-24 h after ozone SD-282 significantly inhibited ozone-induced increases in phosphorylated p38 MAPK expression, and in cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and IL-1beta but not MIP-1alpha gene expression. We conclude that p38 MAPK is involved in ozone-induced airway hyperresponsiveness and lung neutrophilia. Inhibition of p38 MAPK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and airway hyperresponsiveness.
A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression
Publisher: Proceedings of the National Academy of Sciences
Date: 17-06-2002
Abstract: The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.
Histone deacetylase 2–mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression
Publisher: Rockefeller University Press
Date: 27-12-2005
DOI: 10.1084/JEM.20050466
Abstract: Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-κB–mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1β–induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-κB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-κB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-κB–dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression.
T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients
Publisher: Oxford University Press (OUP)
Date: 29-04-2009
DOI: 10.1111/J.1365-2249.2009.03965.X
Abstract: There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin (IL)-17 as their effector cytokine under the control of IL-22 and IL-23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)-17A, IL-17F, IL-21, IL-22 and IL-23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age-matched control subjects. The expression of IL-17A, IL-17F, IL-21, IL-22, IL-23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL-22+ and IL-23+ immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL-17A+ and IL-22+ immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non-smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL-22+ cells correlated significantly with the number of both CD4+ and CD8+ cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL-17A and IL-22. Increased expression of the Th17-related cytokines IL-17A, IL-22 and IL-23 in COPD patients may reflect their involvement, and that of specific IL-17-producing cells, in driving the chronic inflammation seen in COPD.
Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2020
DOI: 10.1101/2020.08.31.20169946
Abstract: The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. A subset of COVID-19 patients progresses to severe disease, with high mortality and limited treatment options. Detailed knowledge of the expression regulation of genes required for viral entry into respiratory epithelial cells is urgently needed. Here we assess the expression patterns of genes required for SARS-CoV-2 entry into cells, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using s les collected from the upper (nasal) and lower airways (bronchi). Genes encoding viral receptors and activating protease are increased in the nose compared to the bronchi in matched s les and associated with the proportion of secretory epithelial cells in cellular deconvolution analyses. Current or ex-smoking was found to increase expression of these genes only in lower airways, which was associated with a significant increase in the predicted proportion of goblet cells. Both acute and second hand smoke exposure were found to increase ACE2 expression while inhaled corticosteroids decrease ACE2 expression in the lower airways. A strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified. Genes associated with SARS-CoV-2 viral entry into cells are high in upper airways, but strongly increased in lower airways by smoke exposure. In contrast, ICS decreases ACE2 expression, indicating that inhaled corticosteroids are unlikely to increase the risk for more severe COVID-19 disease. This work was supported by a Seed Network grant from the Chan Zuckerberg Initiative to M.C.N. and by the European Union’s H2020 Research and Innovation Program under grant agreement no. 874656 (discovAIR) to M.C.N. U BIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No. 115010), resources from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution ( www.imi.europa.eu ). Longfonds Junior Fellowship. We acknowledge the contribution of the whole U-BIOPRED team as listed in the Appendix S1.’ SDB, FM and RFS would like to thank the Helmholtz Association, Germany, for support.” NIH K08HL146943 Parker B. Francis Fellowship ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. RCR is part funded by Cancer Research UK Cambridge Centre and the Cambridge NIHR Biomedical Research Centre. BAP was funded by programme support from Cancer Research UK. The CRUKPAP Study was supported by the CRUK Cambridge Cancer Centre, by the NIHR Cambridge Biomedical Research Centre and by the Cambridge Bioresource. PIAMA was supported by The Netherlands Organization for Health Research and Development The Netherlands Organization for Scientific Research The Netherlands Lung Foundation (with methylation studies supported by AF 4.1.14.001) The Netherlands Ministry of Spatial Planning, Housing, and the Environment and The Netherlands Ministry of Health, Welfare, and Sport. Dr. Qi is supported by a grant from the China Scholarship Council.
Clinical characteristics of re-positive COVID-19 patients in Huangshi, China: A retrospective cohort study
Publisher: Public Library of Science (PLoS)
Date: 04-11-2020
A new ataxia-telangiectasia mutation in an 11-year-old female
Publisher: Springer Science and Business Media LLC
Date: 09-05-2017
RETRACTED: Kinase inhibitors and airway inflammation
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.EJPHAR.2005.12.054
Abstract: Kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function and airway remodelling. Important kinases such as Inhibitor of kappaB kinase (IKK)2, mitogen activated protein (MAP) kinases and phsopho-inositol (PI)3 kinase regulate inflammation either through activation of pro-inflammatory transcription factors such as activating protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), which are activated in airway disease, or through regulation of mRNA half-life. Selective kinase inhibitors have been developed which reduce inflammation and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or over active in disease should allow for selective treatment of respiratory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukaemia viral oncogene (Abl) kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myelogenous leukaemia. Encouraging data from animal models and primary cells and early Phase I and II studies in other diseases suggest that inhibitors of p38 MAP kinase and IKK2 may prove to be useful novel therapies in the treatment of severe asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and other inflammatory airway diseases.
Bronchodilatory Effect of the PPAR-γ Agonist Rosiglitazone in Smokers With Asthma
Publisher: Springer Science and Business Media LLC
Date: 08-04-2009
DOI: 10.1038/CLPT.2009.41
Abstract: Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist would be superior for the clinical treatment of these asthma patients. Forty-six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 microg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced expiratory volume in 1 s (FEV(1)) = 183 ml, P = 0.051 forced expiratory flow between 25 and 75% of the forced vital capacity (FEF(25-75)) = 0.24 l/s, P = 0.030) as compared with inhaled beclometasone dipropionate. Further trials using PPAR-gamma agonists in steroid-resistant airway disease are indicated.
S38 The Brd4 Inhibitor, Jq1 Decreases Proliferation And Arrests The Cell Cycle Of Pulmonary Vascular Cells: Implications For Pulmonary Arterial Hypertension
Publisher: BMJ
Date: 10-11-2014
Animal models of COPD: What do they tell us?
Publisher: Wiley
Date: 12-10-2017
DOI: 10.1111/RESP.12908
Abstract: COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.
NF-κB Function in Inflammation, Cellular Stress and Disease
Publisher: Elsevier
Date: 2002
Corticosteroid resistance in asthma: Cellular and molecular mechanisms
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.MAM.2021.100969
Abstract: Inhaled glucocorticoids (GCs) are drugs widely used as treatment for asthma patients. They prevent the recruitment and activation of lung immune and inflammatory cells and, moreover, have profound effects on airway structural cells to reverse the effects of disease on airway inflammation. GCs bind to a specific receptor, the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily and modulates pro- and anti-inflammatory gene transcription through a number of distinct and complementary mechanisms. Targets genes include many pro-inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. Inhaled GCs are very effective for most asthma patients with little, if any, systemic side effects depending upon the dose. However, some patients show poor asthma control even after the administration of high doses of topical or even systemic GCs. Several mechanisms relating to inflammation have been considered to be responsible for the onset of the relative GC resistance observed in these patients. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness.
New drugs under development for COPD
Publisher: Informa UK Limited
Date: 29-09-2020
Oxidative stress and redox regulation of lung inflammation in COPD
Publisher: European Respiratory Society (ERS)
Date: 07-2006
DOI: 10.1183/09031936.06.00053805
Abstract: Reactive oxygen species, either directly or via the formation of lipid peroxidation products, may play a role in enhancing inflammation through the activation of stress kinases (c-Jun activated kinase, extracellular signal-regulated kinase, p38) and redox-sensitive transcription factors, such as nuclear factor (NF)-kappaB and activator protein-1. This results in increased expression of a battery of distinct pro-inflammatory mediators. Oxidative stress activates NF-kappaB-mediated transcription of pro-inflammatory mediators either through activation of its activating inhibitor of kappaB-alpha kinase or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-kappaB-co-activator complex formation results in targeted increases in histone modifications, such as acetylation leading to inflammatory gene expression. Emerging evidence suggests the glutathione redox couple may entail dynamic regulation of protein function by reversible disulphide bond formation on kinases, phosphatases and transcription factors. Oxidative stress also inhibits histone deacetylase activity and in doing so further enhances inflammatory gene expression and may attenuate glucocorticoid sensitivity. The antioxidant/anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn, erdosteine), dietary polyphenols (curcumin-diferuloylmethane, cathechins/quercetin and reserveratol), specific spin traps, such as alpha-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (extracellular superoxide dismutase (SOD) mimetic, SOD mimetic M40419 and SOD, and catalase manganic salen compound, eukarion-8), porphyrins (AEOL 10150 and AEOL 10113) and theophylline have all been shown to play a role in either controlling NF-kappaB activation or affecting histone modifications with subsequent effects on inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both key signal transduction pathways and histone modifications involved in lung inflammation. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in chronic obstructive pulmonary disease are also discussed.
Chromosome 17q21 SNP and severe asthma
Publisher: Springer Science and Business Media LLC
Date: 28-10-2010
DOI: 10.1038/JHG.2010.134
Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future
Publisher: Springer Science and Business Media LLC
Date: 26-06-2009
DOI: 10.1007/S00228-009-0682-Z
Abstract: Inhaled corticosteroid (ICS) therapy in combination with long-acting beta-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting beta-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 mug daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 mug daily, and addition of the LABA formoterol to budesonide (800 mug) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV(1) and the rate of exacerbations. A reduction in the rate of decline in FEV(1) of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases.
Neutrophil Elastase Represses IL-8/CXCL8 Synthesis in Human Airway Smooth Muscle Cells through Induction of NF-κB Repressing Factor
Publisher: The American Association of Immunologists
Date: 07-2009
Abstract: NF-κB repressing factor (NRF), a nuclear inhibitor of NF-κB, is constitutively expressed and is implicated in the basal silencing of specific NF-κB targeting genes, including IFN-β, IL-8/CXCL8, and iNOS. Little is known about the regulation of NRF and its role in response to stimuli. Airway smooth muscle (ASM) is a rich source of inflammatory mediators that may regulate the development and progression of airway inflammation. We have previously reported that NE activates NF-κB in primary human ASM (hASM), leading to induction of TGF-β1. In this study, we describe that, instead of inducing the NF-κB response gene IL-8/CXCL8, NE suppressed IL-8/CXCL8 release and mRNA expression in hASM cells. Transcriptional blockade studies using actinomycin D revealed a similar degradation rate of IL-8/CXCL8 mRNA in the presence or absence of NE, suggesting an involvement at the transcription level. Mechanistically, the NE repressive effect was mediated by inducing NRF, as shown by RT-PCR and Western blotting, which was subsequently recruited to the native IL-8/CXCL8 promoter leading to removal of RNA polymerase II from the promoter, as demonstrated by chromatin immunoprecipitation assays. Knockdown of NRF by small interfering RNA prevented NE-induced suppression of IL-8/CXCL8 expression. In contrast, NE did not induce NRF expression in A549 and Beas-2B cells, where NE only stimulates NF-κB activation and IL-8/CXCL8 induction. Forced expression of NRF in A549 cells by an NRF expression plasmid suppressed IL-8/CXCL8 expression. Hence, we describe a novel negative regulatory mechanism of NE-induced NRF, which is restricted to hASM and mediates the suppression of IL-8/CXCL8 expression.
Analysis of Transcription Factor Activation: NFκ B as Regulator of Inflammatory Genes in Epithelial Cells
Publisher: Humana Press
Date: 2000
DOI: 10.1385/1-59259-072-1:143
Abstract: In addition to being essential for differentiation and maturation, regulated gene expression governs many cellular responses to their local environment. For ex le, cytokines, viral infection, and numerous other inflammatory stimuli elicit the expression of specific response genes. Such signals are generally.
Effect of noradrenaline and isoproterenol on lipopolysaccharide-induced tumor necrosis factor-alpha production in whole blood from patients with chronic heart failure and the role of beta-adrenergic r
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.AMJCARD.2004.12.022
Abstract: Increased levels of tumor necrosis factor-alpha (TNF-alpha) correlate with poor prognoses in chronic heart failure (CHF). This study demonstrated that noradrenaline and isoproterenol inhibit TNF-alpha production in patients with CHF in ex vivo whole blood in a dose-dependent fashion. The beta-blocker bisoprolol abolishes this effect.
Role of Metabolic Reprogramming in Pulmonary Innate Immunity and Its Impact on Lung Diseases
Publisher: S. Karger AG
Date: 29-11-2019
DOI: 10.1159/000504344
Abstract: Lung innate immunity is the first line of defence against inhaled allergens, pathogens and environmental pollutants. Cellular metabolism plays a key role in innate immunity. Catabolic pathways, including glycolysis and fatty acid oxidation (FAO), are interconnected with biosynthetic and redox pathways. Innate immune cell activation and differentiation trigger extensive metabolic changes that are required to support their function. Pro-inflammatory polarisation of macrophages and activation of dendritic cells, mast cells and neutrophils are associated with increased glycolysis and a shift towards the pentose phosphate pathway and fatty acid synthesis. These changes provide the macromolecules required for proliferation and inflammatory mediator production and reactive oxygen species for anti-microbial effects. Conversely, anti-inflammatory macrophages use primarily FAO and oxidative phosphorylation to ensure efficient energy production and redox balance required for prolonged survival. Deregulation of metabolic reprogramming in lung diseases, such as asthma and chronic obstructive pulmonary disease, may contribute to impaired innate immune cell function. Understanding how innate immune cell metabolism is altered in lung disease may lead to identification of new therapeutic targets. This is important as drugs targeting a number of metabolic pathways are already in clinical development for the treatment of other diseases such as cancer.
Immune Response to Mycobacterium tuberculosis Infection in the Parietal Pleura of Patients with Tuberculous Pleurisy
Publisher: Public Library of Science (PLoS)
Date: 28-07-2011
Effect of mesenchymal stem cell‐derived exosomes on the induction of mouse tolerogenic dendritic cells
Publisher: Wiley
Date: 11-02-2020
DOI: 10.1002/JCP.29601
Abstract: Dendritic cells (DCs) orchestrate innate inflammatory responses and adaptive immunity through T‐cell activation via direct cell–cell interactions and/or cytokine production. Tolerogenic DCs (tolDCs) help maintain immunological tolerance through the induction of T‐cell unresponsiveness or apoptosis, and generation of regulatory T cells. Mesenchymal stromal cells (MSCs) are adult multipotent cells located within the stroma of bone marrow (BM), but they can be isolated from virtually all organs. Extracellular vesicles and exosomes are released from inflammatory cells and act as messengers enabling communication between cells. To investigate the effects of MSC‐derived exosomes on the induction of mouse tolDCs, murine adipose‐derived MSCs were isolated from C57BL/6 mice and exosomes isolated by ExoQuick‐TC kits. BM‐derived DCs (BMDCs) were prepared and cocultured with MSCs‐derived exosomes (100 μg/ml) for 72 hr. Mature BMDCs were derived by adding lipopolysaccharide (LPS 0.1μg/ml) at Day 8 for 24 hr. The study groups were ided into (a) immature DC (iDC, Ctrl), (b) iDC + exosome (Exo), (c) iDC + LPS (LPS), and (d) iDC + exosome + LPS (EXO + LPS). Expression of CD11c, CD83, CD86, CD40, and MHCII on DCs was analyzed at Day 9. DC proliferation was assessed by coculture with carboxyfluorescein succinimidyl ester‐labeled BALB/C‐derived splenocytes p. Interleukin‐6 (IL‐6), IL‐10, and transforming growth factor‐β (TGF‐β) release were measured by enzyme‐linked immunosorbent assay. MSC‐derived exosomes decrease DC surface marker expression in cells treated with LPS, compared with control cells ( ≤ .05). MSC‐derived exosomes decrease IL‐6 release but augment IL‐10 and TGF‐β release ( p ≤ .05). Lymphocyte proliferation was decreased ( p ≤ .05) in the presence of DCs treated with MSC‐derived exosomes. CMSC‐derived exosomes suppress the maturation of BMDCs, suggesting that they may be important modulators of DC‐induced immune responses.
Bovis Bacillus Calmette–Guerin (BCG) infection induces exosomal miRNA release by human macrophages
Publisher: Springer Science and Business Media LLC
Date: 12-05-2017
β-adrenoceptor agonists interfere with glucocorticoid receptor DNA binding in rat lung
Publisher: Elsevier BV
Date: 04-1995
DOI: 10.1016/0922-4106(95)90104-3
Abstract: Inhaled beta 2-adrenoceptor agonists are the most effective bronchodilator treatment in asthma, yet paradoxically high doses may be associated with increased asthma morbidity and mortality. Steroids are the most effective therapy in controlling asthmatic inflammation and act by binding to specific sequences of DNA (GRE), thus modulating gene transcription. We report that in rat lung, the beta 2-adrenoceptor agonists, salbutamol and fenoterol, decrease the binding of glucocorticoid receptors to GRE, by 46 +/- 4% although it has no effect on the affinity or number of glucocorticoid receptors. The inhibition of GRE binding by salbutamol is concentration-dependent, can be blocked by propranolol and is seen following forskolin treatment. This effect appears to be due to an interaction between the glucocorticoid receptor and the transcription factor, cAMP response element binding protein (CREB), which is activated by high concentrations of beta 2-adrenoceptor agonists. We suggest that by this mechanism high doses of inhaled beta 2-adrenoceptor agonists may inhibit the anti-inflammatory effects of endogenous glucocorticoids and exogenous corticosteroids used for asthma therapy.
S50 Airway Smooth Muscle Inflammation Is Controlled By Microrna-145 Targeting Of Smad3 In Copd
Publisher: BMJ
Date: 10-11-2014
Relationship between Exhaled Nitric Oxide and Mucosal Eosinophilic Inflammation in Children with Difficult Asthma, after Treatment with Oral Prednisolone
Publisher: American Thoracic Society
Date: 15-10-2001
DOI: 10.1164/AJRCCM.164.8.2101145
Abstract: Exhaled nitric oxide (FE(NO)) has been proposed as a noninvasive marker of airway inflammation in asthma, and may reflect airway eosinophilia. We examined the relationship between FE(NO) and eosinophilic inflammation in endobronchial biopsies from 31 children with difficult asthma (mean age [range] 11.9 [6-17] yr), following 2 wk of prednisolone (40 mg/d). Endobronchial biopsy was also performed in seven children without asthma. Biopsy eosinophils were detected using antibody to major basic protein, and point-counting used to derive an "eosinophil score." FE(NO) readings and suitable biopsies for analysis were both obtained in 21 of 31 children with asthma. Adherence to prednisolone was demonstrated in 17 of these 21. Within this group, there was a correlation between FE(NO) and eosinophil score (r = 0.54, p = 0.03). The relationship was strongest in patients with persistent symptoms after prednisolone, in whom FE(NO) > 7 ppb was associated with a raised eosinophil score. For all patients, FE(NO) < 7 ppb was associated with an eosinophil score within the nonasthmatic range, regardless of symptoms. We propose that FE(NO) is associated with eosinophilic inflammation in children with difficult asthma, following prednisolone, and may help in identifying patients in whom persistent symptoms are associated with airway eosinophilia.
Histone Deacetylase Activity and COPD
Publisher: Massachusetts Medical Society
Date: 04-08-2005
The Immune Response and Immunopathology of COVID-19
Publisher: Frontiers Media SA
Date: 26-08-2020
Serum Exosomal miRNAs Are Associated with Active Pulmonary Tuberculosis
Publisher: Hindawi Limited
Date: 11-02-2019
DOI: 10.1155/2019/1907426
Abstract: Introduction . Tuberculosis (TB) remains a major threat to human health. Due to the limited accuracy of the current TB diagnostic tests, it is critical to determine novel biomarkers for this disease. Circulating exosomes have been used as diagnostic biomarkers in various diseases. Objective of the Study . In this pilot study, we examined the expression of miRNAs as biomarker candidates for the diagnosis of TB infection. Methods . Serum-derived exosomes were isolated from TB patients and matched control subjects. The expression of miR-484, miR-425, and miR-96 was examined by RT-PCR methods. Results . The expression of miR-484, miR-425, and miR-96 were significantly increased in serum of TB patients which correlated with the TB infection level. A receiver operating characteristic (ROC) curve analysis showed the diagnostic potency of each in idual serum exosomal miRNA with an area under the curve AUC = 0.72 for miR-484 ( p 0.05 ), 0.66 for miR-425 ( p 0.05 ), and 0.62 for miR-96 ( p 0.05 ). Conclusion . These results demonstrate that exosomal miRNAs have diagnostic potential in active tuberculosis. The diagnostic power may be improved when combined with conventional diagnostic markers.
Transcriptomic gene signatures associated with persistent airflow limitation in patients with severe asthma
Publisher: European Respiratory Society (ERS)
Date: 09-2017
DOI: 10.1183/13993003.02298-2016
Abstract: A proportion of severe asthma patients suffers from persistent airflow limitation (PAL), often associated with more symptoms and exacerbations. Little is known about the underlying mechanisms. Here, our aim was to discover unexplored potential mechanisms using Gene Set Variation Analysis (GSVA), a sensitive technique that can detect underlying pathways in heterogeneous s les.Severe asthma patients from the U-BIOPRED cohort with PAL (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio below the lower limit of normal) were compared with those without PAL. Gene expression was assessed on the total RNA of sputum cells, nasal brushings, and endobronchial brushings and biopsies. GSVA was applied to identify differentially enriched predefined gene signatures based on all available gene expression publications and data on airways disease.Differentially enriched gene signatures were identified in nasal brushings (n=1), sputum (n=9), bronchial brushings (n=1) and bronchial biopsies (n=4) that were associated with response to inhaled steroids, eosinophils, interleukin-13, interferon-α, specific CD4
LATE-BREAKING ABSTRACT: Transcriptomic fingerprinting in severe adult-onset asthma shows type2-high and inflammatory-cell gene signatures in the U-BIOPRED cohort
Publisher: European Respiratory Society
Date: 09-2015
ERS/EAACI statement on adherence to international adult asthma guidelines
Publisher: European Respiratory Society (ERS)
Date: 15-09-2021
DOI: 10.1183/16000617.0132-2021
Abstract: Guidelines aim to standardise and optimise asthma diagnosis and management. Nevertheless, adherence to guidelines is suboptimal and may vary across different healthcare professional (HCP) groups. Further to these concerns, this European Respiratory Society (ERS)/European Academy of Allergy and Clinical Immunology (EAACI) statement aims to: 1) evaluate the understanding of and adherence to international asthma guidelines by HCPs of different specialties via an international online survey and 2) assess strategies focused at improving implementation of guideline-recommended interventions, and compare process and clinical outcomes in patients managed by HCPs of different specialties via systematic reviews. The online survey identified discrepancies between HCPs of different specialties which may be due to poor dissemination or lack of knowledge of the guidelines but also a reflection of the adaptations made in different clinical settings, based on available resources. The systematic reviews demonstrated that multifaceted quality improvement initiatives addressing multiple challenges to guidelines adherence are most effective in improving guidelines adherence. Differences in outcomes between patients managed by generalists or specialists should be further evaluated. Guidelines need to consider the heterogeneity of real-life settings for asthma management and tailor their recommendations accordingly. Continuous, multifaceted quality improvement processes are required to optimise and maintain guidelines adherence. Validated referral pathways for uncontrolled asthma or uncertain diagnosis are needed.
Inhibition of ozone-induced lung neutrophilia and nuclear factor-κB binding activity by vitamin A in rat
Publisher: Elsevier BV
Date: 07-1999
DOI: 10.1016/S0014-2999(99)00405-7
Abstract: Vitamin A binds to retinoic acid receptors, which in turn may interact with other transcription factors. We determined its effect (2500 and 5000 IU/kg) on nuclear factor-kappaB binding activity in the lung, airway inflammation and bronchial hyperresponsiveness in rats exposed to ozone. Ozone (3 ppm, 3 h) caused neutrophil influx into bronchoalveolar lavage fluid (16.2+/-0.8 x 10(5) cells/ml, p < 0.01) and bronchial hyperresponsiveness (-logPC200ACh = 2.54+/-0.19, p < 0.05, compared to control animals, respectively). Vitamin A inhibited this neutrophilia dose-dependently together with the increased DNA-binding activity of nuclear factor-KB in lung extracts. Vitamin A did not affect bronchial hyperresponsiveness at both doses. Vitamin A inhibits ozone-induced neutrophilic inflammation through a reduction in nuclear factor-kappaB DNA binding activity.
Transcription Factors
Publisher: Elsevier
Date: 2009
Reduced phagocytic capacity of blood monocyte/macrophages in tuberculosis patients is further reduced by smoking
Publisher: European Respiratory Society
Date: 09-2016
The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD
Publisher: Public Library of Science (PLoS)
Date: 11-01-2016
Differential mast cell activation by transcriptomic signature analysis in the U-BIOPRED severe asthma cohort
Publisher: European Respiratory Society
Date: 07-09-2020
Attenuation of PM2.5-induced alveolar epithelial cells and lung injury through regulation of mitochondrial fission and fusion
Publisher: Springer Science and Business Media LLC
Date: 18-07-2023
DOI: 10.1186/S12989-023-00534-W
Abstract: Exposure to particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM 2.5 ) is a risk factor for developing pulmonary diseases and the worsening of ongoing disease. Mitochondrial fission and fusion are essential processes underlying mitochondrial homeostasis in health and disease. We examined the role of mitochondrial fission and fusion in PM 2.5 -induced alveolar epithelial cell damage and lung injury. Key genes in these processes include dystrophin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) respectively. Alveolar epithelial (A549) cells were treated with PM 2.5 (32 µg/ml) in the presence and absence of M i-1 (10µM, a DRP1 inhibitor) or BGP-15 (10µM, an OPA1 activator). Results were validated using DRP1-knockdown (KD) and OPA1-overexpression (OE). Mice were injected intraperitoneally with M i-1 (20 mg/kg), BGP-15 (20 mg/kg) or distilled water (control) one hour before intranasal instillation of PM 2.5 (7.8 mg/kg) or distilled water for two consecutive days. PM 2.5 exposure of A549 cells caused oxidative stress, enhanced inflammation, necroptosis, mitophagy and mitochondrial dysfunction indicated by abnormal mitochondrial morphology, decreased mitochondrial membrane potential (ΔΨm), reduced mitochondrial respiration and disrupted mitochondrial fission and fusion. Regulating mitochondrial fission and fusion pharmacologically using M i-1 and BGP-15 and genetically using DRP1-KD and OPA1-OE prevented PM 2.5 -induced celluar damage in A549 cells. M i-1 and BGP-15 attenuated PM 2.5 -induced acute lung injury in mice. Increased mitochondrial fission and decreased mitochondrial fusion may underlie PM 2.5 -induced alveolar epithelial cell damage in vitro and lung injury in vivo.
Related Organisations
University Of London
Location: United Kingdom of Great Britain and Northern Ireland
Imperial College London
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
Discovery Projects - Grant ID: DP200101058
Start Date: 2020
End Date: 06-2023
Amount: $500,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP190100091
Start Date: 08-2019
End Date: 06-2023
Amount: $441,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP230101156
Start Date: 07-2023
End Date: 06-2026
Amount: $702,705.00
Funder: Australian Research Council
View Funded Activity