ORCID Profile
0000-0002-7122-9262
Current Organisations
Woolcock Institute of Medical Research
,
University of Technology Sydney
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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.
Cellular Interactions (incl. Adhesion, Matrix, Cell Wall) | Pharmacology and Pharmaceutical Sciences | Pharmaceutical Sciences | Biochemistry and Cell Biology | Nonlinear Optics and Spectroscopy | Colloid and Surface Chemistry | Biological Physics |
Respiratory System and Diseases (incl. Asthma) | Expanding Knowledge in the Physical Sciences | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences
Publisher: Elsevier BV
Date: 04-2023
Publisher: Public Library of Science (PLoS)
Date: 18-08-2014
Publisher: Springer Science and Business Media LLC
Date: 06-02-2018
Publisher: Springer Singapore
Date: 2020
Publisher: Future Medicine Ltd
Date: 05-2022
Publisher: Springer Science and Business Media LLC
Date: 03-06-2022
Publisher: Elsevier BV
Date: 09-2019
Publisher: Frontiers Media SA
Date: 08-02-2023
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.PUPT.2012.06.011
Abstract: Phenotypic changes in airway smooth muscle are integral to the pathophysiological changes that constitute asthma - namely inflammation, airway wall remodelling and bronchial hyperresponsiveness. In vitro and in vivo studies have shown that the proliferative, secretory and contractile functions of airway smooth muscle are dysfunctional in asthma. These functions can be modulated by various mediators whose levels are altered in asthma, derived from inflammatory cells or produced by airway smooth muscle itself. In this review, we describe the emerging roles of the CXC chemokines (GROs, IP-10), Th17-derived cytokines (IL-17, IL-22) and semaphorins, as well as the influence of viral infection on airway smooth muscle function, with a view to identifying new opportunities for therapeutic intervention in asthma.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2015
DOI: 10.1038/SREP09496
Abstract: Fibulin-1 is an extracellular matrix (ECM) protein, levels of which are elevated in serum and lung tissue from patients with idiopathic pulmonary fibrosis compared to healthy volunteers. Inhibition of fibulin-1C, one of four fibulin-1 isoforms, reduced proliferation and wound healing in human airway smooth muscle (ASM) cells. This study identified the bioactive region/s of fibulin-1C which promotes fibrosis. Seven fibulin-1C peptides were synthesized and used to pre-coat tissue culture plates before lung derived ASM cells and fibroblasts from patients with pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD) or neither disease (Control) were plated. Peptide effects on in vitro measures of fibrosis: cell attachment, proliferation and viability and ECM deposition, were examined. Among these peptides, peptide 1C1 (FBLN1C1) enhanced ASM cell and fibroblast attachment. FBLN1C1 increased mitochondrial activity and proliferation in fibroblasts. In addition, FBLN1C1 stimulated fibulin1 deposition in PF and COPD fibroblasts and augmented fibronectin and perlecan deposition in all three groups. Peptides FBLN1C2 to FBLN1C7 had no activity. The active fibulin-1C peptide identified in this study describes a useful tool for future studies. Ongoing investigation of the role of fibulin-1 may reveal the mechanisms underlying the pathphysiology of chronic lung diseases.
Publisher: Elsevier BV
Date: 04-2023
Publisher: European Respiratory Society (ERS)
Date: 12-2019
DOI: 10.1183/20734735.0254-2019
Abstract: Eosinophils are increasingly being recognised as an important characteristic feature of COPD. Patients with COPD and eosinophilic inflammation tend to respond to steroid therapy however, many questions remain regarding the optimum measurement. Eosinophilic inflammation may be defined based on various s ling techniques, including eosinophil levels in blood, sputum, bronchoalveolar lavage or biopsy, which leads to inconsistencies in its definition. Blood eosinophils may increase in conjunction with sputum eosinophils during COPD exacerbations and therefore may be a good surrogate marker of airway eosinophilic inflammation. However, the timing of the blood eosinophil measurement, the stability of the eosinophil count and the threshold used in different studies are variable. The use of blood eosinophil count to direct biological therapies in COPD has also had variable outcomes. Eosinophilic inflammation has an important role in COPD management however, its use as the optimum biomarker still needs further investigation. Eosinophilia may play a significant role in the pathogenesis of COPD. Eosinophilic inflammation in COPD can be steroid responsive however, eosinophilic inflammation is variable, and caution needs to be taken with measurements and the thresholds used. The long-term effects of reducing eosinophil levels in COPD is unclear. To explore current knowledge of eosinophils in COPD. To explore the relationship between eosinophilia and corticosteroid use. To understand the limitations of assessing and using eosinophilia in COPD.
Publisher: American Society for Clinical Investigation
Date: 22-08-2019
Publisher: American Thoracic Society
Date: 10-2013
Publisher: Wiley
Date: 03-07-2014
DOI: 10.1111/ALL.12449
Abstract: Asthma is a widespread chronic health problem exacerbated by common viral and bacterial infections. Further research is required to understand how infection worsens asthma control in order to advance therapeutic options in the future. Recent research has revealed that β2 -adrenergic receptor (β2 -AR) agonists lose bronchodilatory efficacy because the receptor-mediated molecular pathways responsible for their beneficial actions are desensitized by infection. To date, most studies have focussed on viral infection, leaving the impact of bacterial infection on β2 -AR desensitization relatively under-investigated. We address this in this study. Utilizing an in vitro model of bacterial exacerbation in airway smooth muscle (ASM) cells, we show that activation of toll-like receptor 2 (TLR2 mimicking bacterial infection) in the presence of an inflammatory stimulus leads to β2 -AR desensitization. This occurs via TLR2-dependent upregulation of cyclooxygenase 2 (COX-2) mRNA expression and increased secretion of PGE2 . Importantly, PGE2 causes heterologous β2 -AR desensitization and reduces cAMP production in response to short-acting (salbutamol) and long-acting (formoterol) β2 -agonists. Thus, bacterial infectious stimuli act in a PGE2 -dependent manner to severely curtail the beneficial actions of β2 -agonists. The impact of β2 -AR desensitization is demonstrated by reduced gene expression of the critical anti-inflammatory molecule MKP-1 in response to β2 -agonists, as well as impaired bronchodilation in a mouse lung slices. Taken together, our results show that, like viruses, bacteria induce prostanoid-dependent β2 -AR desensitization on ASM cells. Notably, COX-2 inhibition with the specific inhibitor celecoxib represses PGE2 secretion, presenting a feasible pharmacological option for treatment of infectious exacerbation in asthma in the future.
Publisher: American Thoracic Society
Date: 03-2018
Publisher: American Society for Clinical Investigation
Date: 08-02-2018
Publisher: IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 22-03-2022
DOI: 10.1007/S10787-022-00968-2
Abstract: The chronic respiratory non-communicable diseases, asthma and chronic obstructive pulmonary disease (COPD) are among the leading causes of global mortality and morbidity. In iduals suffering from these diseases are particularly susceptible to respiratory infections caused by bacterial and/or viral pathogens, which frequently result in exacerbation of symptoms, lung function decline, frequent hospital emergency visits and increased socioeconomic burden. Human rhinoviruses (HRV) remain the major viral pathogen group implicated in exacerbations of both asthma and COPD. The rhinoviral entry into the host lung epithelium is facilitated primarily by the adhesion site (“receptor”) intercellular adhesion molecule-1 (ICAM-1), coincidentally expressed on the respiratory epithelium in these conditions. Multiple observations of increased airway ICAM-1 protein in asthmatics, smokers and smoking-related COPD have been recorded in the literature. However, the lack of robust therapies for COPD in particular has triggered a renewed interest in assessing receptor antagonism-based anti-viral strategies for treatment of intercurrent viral infections in those with pre-existing chronic lung diseases. Given the crucial role ICAM-1 plays in facilitating HRV adhesion and, thus, transmissibility to the host respiratory system, as well as the up-regulation of ICAM-1 by smoking, we summarize the role of HRV in smoking-induced COPD and especially highlight the role of ICAM-1 in epithelial viral adhesion and chronic lung disease progression. Further, the review also sheds light specifically on evolving precision therapeutic strategies in blocking ICAM-1 for preventing viral adhesion and exacerbations of COPD.
Publisher: Wiley
Date: 23-04-2012
DOI: 10.1002/JCP.23046
Abstract: Transforming growth factor (TGF) β1 increases pro-inflammatory cytokines and contractile protein expression by human airway smooth muscle (ASM) cells, which could augment airway inflammation and hyperresponsiveness. Phosphoinositide 3' kinase (PI3K) is one of the signaling pathways implicated in TGFβ1 stimulation, and may be altered in asthmatic airways. This study compared the expression of PI3K isoforms by ASM cells from donors with asthma (A), chronic obstructive pulmonary disease (COPD), or neither disease (NA), and investigated the role of PI3K isoforms in the production of TGFβ1 induced pro-inflammatory cytokine and contractile proteins in ASM cells. A cells expressed higher basal levels of p110δ mRNA compared to NA and COPD cells however COPD cells produced more p110δ protein. TGFβ1 increased 110δ mRNA expression to the same extent in the three groups. Neither the p110δ inhibitor IC87114 (1, 10, 30 µM), the p110β inhibitor TGX221 (0.1, 1, 10 µM) nor the PI3K pan inhibitor LY294002 (3, 10 µM) had any effect on basal IL-6, calponin or smooth muscle α-actin (α-SMA) expression. However, TGFβ1 increased calponin and α-SMA expression was inhibited by IC87114 and LY294002 in all three groups. IC87114, TGX221, and LY294002 reduced TGFβ1 induced IL-6 release in a dose related manner in all groups of ASM cells. PI3K p110δ is important for TGFβ1 induced production of the contractile proteins calponin and α-SMA and the proinflammatory cytokine IL-6 in ASM cells, and may therefore be relevant as a potential therapeutic target to treat both inflammation and airway remodeling.
Publisher: MDPI AG
Date: 26-04-2023
DOI: 10.3390/V15051065
Abstract: The COVID-19 pandemic caused by SARS-CoV-2 has had a severe impact on people worldwide. The reference genome of the virus has been widely used as a template for designing mRNA vaccines to combat the disease. In this study, we present a computational method aimed at identifying co-existing intra-host strains of the virus from RNA-sequencing data of short reads that were used to assemble the original reference genome. Our method consisted of five key steps: extraction of relevant reads, error correction for the reads, identification of within-host ersity, phylogenetic study, and protein binding affinity analysis. Our study revealed that multiple strains of SARS-CoV-2 can coexist in both the viral s le used to produce the reference sequence and a wastewater s le from California. Additionally, our workflow demonstrated its capability to identify within-host ersity in foot-and-mouth disease virus (FMDV). Through our research, we were able to shed light on the binding affinity and phylogenetic relationships of these strains with the published SARS-CoV-2 reference genome, SARS-CoV, variants of concern (VOC) of SARS-CoV-2, and some closely related coronaviruses. These insights have important implications for future research efforts aimed at identifying within-host ersity, understanding the evolution and spread of these viruses, as well as the development of effective treatments and vaccines against them.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2022
DOI: 10.1007/S11356-022-19158-2
Abstract: Non-small cell lung cancer (NSCLC) is reported to have a high incidence rate and is one of the most prevalent types of cancer contributing towards 85% of all incidences of lung cancer. Berberine is an isoquinoline alkaloid which offers a broad range of therapeutical and pharmacological actions against cancer. However, extremely low water solubility and poor oral bioavailability have largely restricted its therapeutic applications. To overcome these limitations, we formulated berberine-loaded liquid crystalline nanoparticles (LCNs) and investigated their in vitro antiproliferative and antimigratory activity in human lung epithelial cancer cell line (A549). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), trypan blue staining, and colony forming assays were used to evaluate the anti-proliferative activity, while scratch wound healing assay and a modified Boyden chamber assay were carried out to determine the anti-migratory activity. We also investigated major proteins associated with lung cancer progression. The developed nanoparticles were found to have an average particle size of 181.3 nm with spherical shape, high entrapment efficiency (75.35%) and have shown sustained release behaviour. The most remarkable findings reported with berberine-loaded LCNs were significant suppression of proliferation, inhibition of colony formation, inhibition of invasion or migration via epithelial mesenchymal transition, and proliferation related proteins associated with cancer progression. Our findings suggest that anti-cancer compounds with the problem of poor solubility and bioavailability can be overcome by formulating them into nanotechnology-based delivery systems for better efficacy. Further in-depth investigations into anti-cancer mechanistic research will expand and strengthen the current findings of berberine-LCNs as a potential NSCLC treatment option.
Publisher: Public Library of Science (PLoS)
Date: 26-12-2013
Publisher: European Respiratory Society (ERS)
Date: 18-09-2014
DOI: 10.1183/09031936.00047714
Abstract: Asthma is a chronic inflammatory disease of the airways in which the majority of patients respond to treatment with corticosteroids and β 2 -adrenoceptor agonists. Acute exacerbations of asthma substantially contribute to disease morbidity, mortality and healthcare costs, and are not restricted to patients who are not compliant with their treatment regimens. Given that respiratory viral infections are the principal cause of asthma exacerbations, this review article will explore the relationship between viral infections and asthma, and will put forward hypotheses as to why virus-induced exacerbations occur. Potential mechanisms that may explain why current therapeutics do not fully inhibit virus-induced exacerbations, for ex le, β 2 -adrenergic desensitisation and corticosteroid insensitivity, are explored, as well as which aspects of virus-induced inflammation are likely to be attenuated by current therapy.
Publisher: AME Publishing Company
Date: 03-2019
Publisher: MDPI AG
Date: 09-05-2022
DOI: 10.3390/MOLECULES27093038
Abstract: The inflammatory response is a central aspect of the human immune system that acts as a defense mechanism to protect the body against infections and injuries. A dysregulated inflammatory response is a major health concern, as it can disrupt homeostasis and lead to a plethora of chronic inflammatory conditions. These chronic inflammatory diseases are one of the major causes of morbidity and mortality worldwide and the need for them to be managed in the long term has become a crucial task to alleviate symptoms and improve patients’ overall quality of life. Although various synthetic anti-inflammatory agents have been developed to date, these medications are associated with several adverse effects that have led to poor therapeutic outcomes. The hunt for novel alternatives to modulate underlying chronic inflammatory processes has unveiled nature to be a plentiful source. One such ex le is agarwood, which is a valuable resinous wood from the trees of Aquilaria spp. Agarwood has been widely utilized for medicinal purposes since ancient times due to its ability to relieve pain, asthmatic symptoms, and arrest vomiting. In terms of inflammation, the major constituent of agarwood, agarwood oil, has been shown to possess multiple bioactive compounds that can regulate molecular mechanisms of chronic inflammation, thereby producing a multitude of pharmacological functions for treating various inflammatory disorders. As such, agarwood oil presents great potential to be developed as a novel anti-inflammatory therapeutic to overcome the drawbacks of existing therapies and improve treatment outcomes. In this review, we have summarized the current literature on agarwood and its bioactive components and have highlighted the potential roles of agarwood oil in treating various chronic inflammatory diseases.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.CBI.2022.110231
Abstract: The human microbiota is fundamental to correct immune system development and balance. Dysbiosis, or microbial content alteration in the gut and respiratory tract, is associated with immune system dysfunction and lung disease development. The microbiota's influence on human health and disease is exerted through the abundance of metabolites produced by resident microorganisms, where short-chain fatty acids (SCFAs) represent the fundamental class. SCFAs are mainly produced by the gut microbiota through anaerobic fermentation of dietary fibers, and are known to influence the homeostasis, susceptibility to and outcome of many lung diseases. This article explores the microbial species found in healthy human gastrointestinal and respiratory tracts. We investigate factors contributing to dysbiosis in lung illness, and the gut-lung axis and its association with lung diseases, with a particular focus on the functions and mechanistic roles of SCFAs in these processes. The key focus of this review is a discussion of the main metabolites of the intestinal microbiota that contribute to host-pathogen interactions: SCFAs, which are formed by anaerobic fermentation. These metabolites include propionate, acetate, and butyrate, and are crucial for the preservation of immune homeostasis. Evidence suggests that SCFAs prevent infections by directly affecting host immune signaling. This review covers the various and intricate ways through which SCFAs affect the immune system's response to infections, with a focus on pulmonary diseases including chronic obstructive pulmonary diseases, asthma, lung cystic fibrosis, and tuberculosis. The findings reviewed suggest that the immunological state of the lung may be indirectly influenced by elements produced by the gut microbiota. SCFAs represent valuable potential therapeutic candidates in this context.
Publisher: American Physiological Society
Date: 07-2020
DOI: 10.1152/AJPLUNG.00028.2020
Abstract: Chronic obstructive pulmonary disease (COPD) is associated with features of accelerated aging, including cellular senescence, DNA damage, oxidative stress, and extracellular matrix (ECM) changes. We propose that these features are particularly apparent in patients with severe, early-onset (SEO)-COPD. Whether fibroblasts from COPD patients display features of accelerated aging and whether this is also present in relatively young SEO-COPD patients is unknown. Therefore, we aimed to determine markers of aging in (SEO)-COPD-derived lung fibroblasts and investigate the impact on ECM. Aging hallmarks and ECM markers were analyzed in lung fibroblasts from SEO-COPD and older COPD patients and compared with fibroblasts from matched non-COPD groups ( n = 9–11 per group), both at normal culture conditions and upon Paraquat-induced senescence. COPD-related differences in senescence and ECM expression were validated in lung tissue. Higher levels of cellular senescence, including senescence-associated β-galactosidase (SA-β-gal)-positive cells (19% for COPD vs. 13% for control) and p16 expression, DNA damage (γ-H2A.X-positive nuclei), and oxidative stress ( MGST1) were detected in COPD compared with control-derived fibroblasts. Most effects were also different in SEO-COPD, with SA-β-gal-positive cells only being significant in SEO-COPD vs. matched controls. Lower decorin expression in COPD-derived fibroblasts correlated with higher p16 expression, and this association was confirmed in lung tissue. Paraquat treatment induced cellular senescence along with clear changes in ECM expression, including decorin. Fibroblasts from COPD patients, including SEO-COPD, display higher levels of cellular senescence, DNA damage, and oxidative stress. The association between cellular senescence and ECM expression changes may suggest a link between accelerated aging and ECM dysregulation in COPD.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 24-02-2011
Abstract: The phosphatidylinositol 3-kinase (PI3K) signal transduction pathway is implicated in the airway remodeling associated with asthma. The class IA PI3K isoforms are known to be activated by growth factors and cytokines. Because this pathway is a possible site of pharmacological intervention for treating the disease, it is important to know which isoforms contribute to this process. Therefore, we used a pharmacological approach to investigate the roles of the three class IA PI3K isoforms (p110α, p110β, and p110δ) in airway remodeling using airway smooth muscle (ASM) cells derived from asthmatic subjects and ASM cells and lung fibroblasts from nonasthmatic subjects. These studies used the inhibitors N'-[(E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-N,2-dimethyl-5-nitrobenzenesulfonohydrazide (PIK75) (which selectively inhibits p110α), 7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (TGX221) (which selectively inhibits p110β), and 2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone (IC87114) (which selectively inhibits p110δ). Cells were stimulated with transforming growth factor-β (TGFβ) and/or 10% fetal bovine serum in the presence or absence of inhibitor or vehicle control (dimethyl sulfoxide). PIK75, but not TGX221 or IC87114, attenuated TGFβ-induced fibronectin deposition in all cell types tested. PIK75 and TGX221 each decreased secretion of vascular endothelial growth factor and interleukin-6 in nonasthmatic ASM cells and lung fibroblasts, whereas TGX221 was not as effective in asthmatic ASM cells. In addition, PIK75 decreased cell survival in TGFβ-stimulated asthmatic, but not nonasthmatic, ASM cells. In conclusion, specific PI3K isoforms may play a role in pathophysiological events relevant to airway wall remodeling.
Publisher: MDPI AG
Date: 25-06-2021
Abstract: Relatively little is known about the transgenerational effects of chronic maternal exposure to low-level traffic-related air pollution (TRAP) on the offspring lung health, nor are the effects of removing such exposure before pregnancy. Female BALB/c mice were exposed to PM2.5 (PM2.5, 5 µg/day) for 6 weeks before mating and during gestation and lactation in a subgroup, PM was removed when mating started to model mothers moving to cleaner areas during pregnancy to protect their unborn child (Pre-exposure). Lung pathology was characterised in both dams and offspring. A subcohort of female offspring was also exposed to ovalbumin to model allergic airways disease. PM2.5 and Pre-exposure dams exhibited airways hyper-responsiveness (AHR) with mucus hypersecretion, increased mitochondrial reactive oxygen species (ROS) and mitochondrial dysfunction in the lungs. Female offspring from PM2.5 and Pre-exposure dams displayed AHR with increased lung inflammation and mitochondrial ROS production, while males only displayed increased lung inflammation. After the ovalbumin challenge, AHR was increased in female offspring from PM2.5 dams compared with those from control dams. Using an in vitro model, the mitochondria-targeted antioxidant MitoQ reversed mitochondrial dysfunction by PM stimulation, suggesting that the lung pathology in offspring is driven by dysfunctional mitochondria. In conclusion, chronic exposure to low doses of PM2.5 exerted transgenerational impairment on lung health.
Publisher: American Thoracic Society
Date: 04-2017
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4TB01928H
Abstract: The impact of a polyunsaturated fatty acid, arachidonic acid (AA), on membrane fluidity of epithelial cells and subsequent modulation of the drug transport was investigated.
Publisher: MDPI AG
Date: 17-02-2023
DOI: 10.3390/NU15041019
Abstract: Chronic obstructive pulmonary disease (COPD) is an irreversible inflammatory respiratory disease characterized by frequent exacerbations and symptoms such as cough and wheezing that lead to irreversible airway damage and hyperresponsiveness. The primary risk factor for COPD is chronic cigarette smoke exposure, which promotes oxidative stress and a general pro-inflammatory condition by stimulating pro-oxidant and pro-inflammatory pathways and, simultaneously, inactivating anti-inflammatory and antioxidant detoxification pathways. These events cause progressive damage resulting in impaired cell function and disease progression. Treatments available for COPD are generally aimed at reducing the symptoms of exacerbation. Failure to regulate oxidative stress and inflammation results in lung damage. In the quest for innovative treatment strategies, phytochemicals, and complex plant extracts such as agarwood essential oil are promising sources of molecules with antioxidant and anti-inflammatory activity. However, their clinical use is limited by issues such as low solubility and poor pharmacokinetic properties. These can be overcome by encapsulating the therapeutic molecules using advanced drug delivery systems such as polymeric nanosystems and nanoemulsions. In this study, agarwood oil nanoemulsion (agarwood-NE) was formulated and tested for its antioxidant and anti-inflammatory potential in cigarette smoke extract (CSE)-treated BCi-NS1.1 airway basal epithelial cells. The findings suggest successful counteractivity of agarwood-NE against CSE-mediated pro-inflammatory effects by reducing the expression of the pro-inflammatory cytokines IL-1α, IL-1β, IL-8, and GDF-15. In addition, agarwood-NE induced the expression of the anti-inflammatory mediators IL-10, IL-18BP, TFF3, GH, VDBP, relaxin-2, IFN-γ, and PDGF. Furthermore, agarwood-NE also induced the expression of antioxidant genes such as GCLC and GSTP1, simultaneously activating the PI3K pro-survival signalling pathway. This study provides proof of the dual anti-inflammatory and antioxidant activity of agarwood-NE, highlighting its enormous potential for COPD treatment.
Publisher: American Thoracic Society
Date: 05-2015
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.EJPHAR.2022.174821
Abstract: Chronic respiratory diseases have collectively become a major public health concern and have now taken form as one of the leading causes of mortality worldwide. Most chronic respiratory diseases primarily occur due to prolonged airway inflammation. In addition, critical environmental factors such as cigarette smoke, industrial pollutants, farm dust, and pollens may also exacerbate such diseases. Moreover, alterations in the genetic sequence of an in idual, abnormalities in the chromosomes or immunosuppression resulting from bacterial, fungal, and viral infections may also play a key role in the pathogenesis of respiratory diseases. Over the years, multiple in vitro models have been employed as the basis of existing as well as emerging advancements in chronic respiratory disease research. These include cell lines, gene expression techniques, single cell RNA sequencing, cytometry, culture techniques, as well as serum/sputum biomarkers that can be used to elucidate the molecular mechanisms underlying these diseases, and to identify novel diagnostic and management options for these diseases. This review summarizes the current understanding of the pathogenesis of various chronic respiratory diseases derived through in vitro experimental models, where the knowledge obtained from these studies can greatly benefit researchers in the discovery and development of novel screening techniques and advanced therapeutic strategies that could be translated into clinical use in the future.
Publisher: Bentham Science Publishers Ltd.
Date: 10-03-2015
DOI: 10.2174/1567201811666140606112918
Abstract: There is an enormous drive to refine therapeutic designs and delivery systems, but in this review we ask if this is always the right direction? We choose to play devil's advocate, and argue that refining drug design is not always needed, and what is actually needed is a greater understanding of the biology of the disease. Here we focus on asthma and the β2-agonist group of bronchodilators as an ex le of how a class of therapeutic has been developed and continues to be developmentally refined. In this review, we define viral-induced exacerbations as the greatest cause of lung attacks and the most crucial time β2-agonist therapy is needed. We explore the reasons why β2-agonist therapy fails in patients with rhinovirus-induced exacerbations, and explain why further "engineered" β2-agonist therapies are likely to continue to fail in this subset of asthmatic population. We justify our perspective by returning to the biology that underlies the cause of disease and highlight the need for "more research" into alternative therapies for this population of asthmatic patients.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Hindawi Limited
Date: 24-10-2011
DOI: 10.1155/2011/457169
Abstract: Rhinovirus-(RV-) induced asthma exacerbations account for high asthma-related health costs and morbidity in Australia. The cellular mechanism underlying this pathology is likely the result of RV-induced nuclear-factor-kappa-B-(NF-κB-) dependent inflammation. NF-κB may also be important in RV replication as inhibition of NF-κB inhibits replication of other viruses such as human immunodeficiency virus and cytomegalovirus. To establish the role of NF-κB inhibitors in RV-induced IL- 6 and IL-8 and RV replication, we used pharmacological inhibitors of NF-κB, and steroids and/or β 2 agonists were used for comparison. Primary human lung fibroblasts were infected with RV-16 in the presence of NF-κB inhibitors: BAY-117085 and dimethyl fumarate β 2 agonist: salmeterol and/or corticosteroids: dexamethasone fluticasone. RV-induced IL-6 and IL-8 and RV replication were assessed using ELISAs and virus titration assays. RV replicated and increased IL-6 and IL-8 release. Salmeterol increased, while dexamethasone and fluticasone decreased RV-induced IL-6 and IL-8 ( P 0.05 ). The NF-κB inhibitor BAY-117085 inhibited only RV-induced IL-6 ( P 0.05 ) and dimethyl fumarate did not alter RV-induced IL-6 and IL-8. Dimethylfumarate increased RV replication whilst other drugs did not alter RV replication. These data suggest that inhibition of NF-κB alone is unlikely to be an effective treatment compared to current asthma therapeutics.
Publisher: Springer Science and Business Media LLC
Date: 26-09-2022
DOI: 10.1007/S00408-022-00570-X
Abstract: Endogenous adenosine 5'-monophosphate (AMP), acetylcholine (ACh), and histamine (HA) are known to be important in bronchial contraction, but their clinical relevance to asthma is poorly understood. We aimed to quantify endogenous AMP, ACh, and HA in induced sputum s les and explore their relationships with asthma control and exacerbations. 20 healthy subjects and 112 asthmatics underwent clinical assessment, sputum induction, and blood s ling. The level of asthma control was determined by the asthma control test (ACT) questionnaire. Asthma exacerbation was evaluated according to the criteria of the American Thoracic Society/European Respiratory Society. Levels of AMP, ACh, and HA in sputum were measured by liquid chromatography coupled to tandem mass spectrometry. IL-β, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17A, TNF-α, IFN-γ, and macrophage-derived chemokine (MDC) were also measured. Compared to healthy controls, asthmatics had higher levels of HA, lower levels of ACh, and similar levels of AMP in induced sputum s les. Compared to controlled asthma (n = 54), uncontrolled asthma (n = 58) showed higher AMP levels (P = 0.002), but similar HA and ACh levels. AMP was negatively correlated with ACT scores (r = - 0.348) and asthma quality of life questionnaire scores (r = - 0.188) and positively correlated with blood monocytes percentage (r = 0.195), sputum MDC (r = 0.214), and IL-6 levels (r = 0.196). Furthermore, AMP was associated with an increased risk of exacerbations in the preceding year. Endogenous AMP, but not ACh or HA, was associated with asthma control, quality of life, and exacerbations in the previous year, which indicates that AMP could be a clinically useful biomarker of asthma.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Springer Science and Business Media LLC
Date: 05-08-2020
DOI: 10.1186/S12950-020-00253-5
Abstract: Cigarette smoke exposure (SE) during pregnancy is the largest modifiable risk factor for the development of lung disorders in offspring. We have previously shown that maternal L-Carnitine treatment can reduce the adverse impacts of maternal SE on renal and brain disorders in offspring. Here, we investigated the effect of maternal L-Carnitine supplementation on lung inflammatory pathways, autophagy, and mitophagy markers in the offspring in response to maternal SE. Female BALB/c mice (8 weeks) were exposed to cigarette smoke for 6 weeks prior to mating, during gestation and lactation. Some of the SE dams were given L-Carnitine supplementation (1.5 mM in drinking water, SE + LC) during gestation and lactation. Lungs from the offspring were studied at birth and adulthood (13 weeks). At birth, in male offspring, there were increased levels of inflammatory markers (phosphorylated(p)-ERK1,2, p-P38 MAPK, p- NF-κB), and inflammasome marker (NLRP3), as well as mitophagy fission marker Drp-1 and autophagosome marker (LC3A/B-II) in the lung. Maternal L-Carnitine supplementation significantly reduced NLRP3 level. In contrast, maternal SE only increased IL1-β in female offspring, which was reversed by maternal L-Carnitine supplementation. At 13 weeks, there was an increase in LC3A/B-II and p- NF-κB in the male SE offspring with reduced p-JNK1,2, which were partially normalised by maternal L-Carnitine treatment. Female offspring were not affected by maternal SE at this age. Maternal SE had adverse impacts on the male offspring’s lung, which were partially alleviated by maternal L-Carnitine supplementation. Females seem to be less affected by the adverse effects of maternal SE.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Informa UK Limited
Date: 24-11-2017
Publisher: Wiley
Date: 22-11-2023
DOI: 10.1111/RESP.14401
Abstract: Smoking disturbs the bronchial-mucus-barrier. This study assesses the cellular composition and gene expression shifts of the bronchial-mucus-barrier with smoking to understand the mechanism of mucosal damage by cigarette smoke exposure. We explore whether single-cell-RNA-sequencing (scRNA-seq) based cellular deconvolution (CD) can predict cell-type composition in RNA-seq data. RNA-seq data of bronchial biopsies from three cohorts were analysed using CD. The cohorts included 56 participants with chronic obstructive pulmonary disease [COPD] (38 smokers 18 ex-smokers), 77 participants without COPD (40 never-smokers 37 smokers) and 16 participants who stopped smoking for 1 year (11 COPD and 5 non-COPD-smokers). Differential gene expression was used to investigate gene expression shifts. The CD-derived goblet cell ratios were validated by correlating with staining-derived goblet cell ratios from the COPD cohort. Statistics were done in the R software (false discovery rate p-value < 0.05). Both CD methods indicate a shift in bronchial-mucus-barrier cell composition towards goblet cells in COPD and non-COPD-smokers compared to ex- and never-smokers. It shows that the effect was reversible within a year of smoking cessation. A reduction of ciliated and basal cells was observed with current smoking, which resolved following smoking cessation. The expression of mucin and sodium channel (ENaC) genes, but not chloride channel genes, were altered in COPD and current smokers compared to never smokers or ex-smokers. The goblet cell-derived staining scores correlate with CD-derived goblet cell ratios. Smoking alters bronchial-mucus-barrier cell composition, transcriptome and increases mucus production. This effect is partly reversible within a year of smoking cessation. CD methodology can predict goblet-cell percentages from RNA-seq.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2018
DOI: 10.1038/S41598-018-24949-0
Abstract: To investigate the effect of maternal MitoQ treatment on renal disorders caused by maternal cigarette smoke exposure (SE). We have demonstrated that maternal SE during pregnancy increases the risk of developing chronic kidney disease (CKD) in adult offspring. Mitochondrial oxidative damage contributes to the adverse effects of maternal smoking on renal disorders. MitoQ is a mitochondria-targeted antioxidant that has been shown to protect against oxidative damage-related pathologies in many diseases. Female Balb/c mice (8 weeks) were ided into Sham (exposed to air), SE (exposed to cigarette smoke) and SEMQ (exposed to cigarette smoke with MitoQ supplemented from mating) groups. Kidneys from the mothers were collected when the pups weaned and those from the offspring were collected at 13 weeks. Maternal MitoQ supplementation during gestation and lactation significantly reversed the adverse impact of maternal SE on offspring’s body weight, kidney mass and renal pathology. MitoQ administration also significantly reversed the impact of SE on the renal cellular mitochondrial density and renal total reactive oxygen species in both the mothers and their offspring in adulthood. Our results suggested that MitoQ supplementation can mitigate the adverse impact of maternal SE on offspring’s renal pathology, renal oxidative stress and mitochondrial density in mice offspring.
Publisher: Public Library of Science (PLoS)
Date: 22-06-2018
Publisher: American Physiological Society
Date: 08-2017
DOI: 10.1152/AJPLUNG.00134.2017
Abstract: Maternal smoking during pregnancy contributes to long-term health problems in offspring, especially respiratory disorders that can manifest in either childhood or adulthood. Receptors for advanced glycation end products (RAGE) are multiligand receptors abundantly localized in the lung, capable of responding to by-products of reactive oxygen species and proinflammatory responses. RAGE signaling is a key regulator of inflammation in cigarette smoking-related pulmonary diseases. However, the impact of maternal cigarette smoke exposure on lung RAGE signaling in the offspring is unclear. This study aims to investigate the effect of maternal cigarette smoke exposure (SE), as well as mitochondria-targeted antioxidant [mitoquinone mesylate (MitoQ)] treatment, during pregnancy on the RAGE-mediated signaling pathway in the lung of male offspring. Female Balb/c mice (8 wk) were ided into a sham group (exposed to air), an SE group (exposed to cigarette smoke), and an SE + MQ group (exposed to cigarette smoke with MitoQ supplement from mating). The lungs from male offspring were collected at 13 wk. RAGE and its downstream signaling, including nuclear factor-κB and mitogen-activated protein kinase family consisting of extracellular signal-regulated kinase 1, ERK2, c-JUN NH 2 -terminal kinase (JNK), and phosphorylated JNK, in the lung were significantly increased in the SE offspring. Mitochondrial antioxidant manganese superoxide dismutase was reduced, whereas IL-1β and oxidative stress response nuclear factor (erythroid-derived 2)-like 2 were significantly increased in the SE offspring. Maternal MitoQ treatment normalized RAGE, IL-1β, and Nrf-2 levels in the SE + MQ offspring. Maternal SE increased RAGE and its signaling elements associated with increased oxidative stress and inflammatory cytokines in offspring lungs, whereas maternal MitoQ treatment can partially normalize these changes.
Publisher: Future Science Ltd
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 09-03-2019
DOI: 10.1007/S00011-019-01224-0
Abstract: Tristetraprolin (TTP) is an anti-inflammatory molecule known to post-transcriptionally regulate cytokine production and is, therefore, an attractive drug target for chronic respiratory diseases driven by inflammation, such as asthma and chronic obstructive pulmonary disease. Our recent in vitro studies in primary human airway smooth (ASM) cells have confirmed the essential anti-inflammatory role played by TTP as a critical partner in a cytokine regulatory network. However, several unanswered questions remain. While prior in vitro studies have suggested that TTP is regulated in a cAMP-mediated manner, raising the possibility that this may be one of the ways in which β
Publisher: Elsevier BV
Date: 10-2021
Publisher: MDPI AG
Date: 28-04-2022
Abstract: Cigarette smoke is considered a primary risk factor for chronic obstructive pulmonary disease. Numerous toxicants present in cigarette smoke are known to induce oxidative stress and airway inflammation that further exacerbate disease progression. Generally, the broncho-epithelial cells and alveolar macrophages exposed to cigarette smoke release massive amounts of oxidative stress and inflammation mediators. Chronic exposure of cigarette smoke leads to premature senescence of airway epithelial cells. This impairs cellular function and ultimately leads to the progression of chronic lung diseases. Therefore, an ideal therapeutic candidate should prevent disease progression by controlling oxidative stress, inflammation, and senescence during the initial stage of damage. In our study, we explored if berberine (an alkaloid)-loaded liquid crystalline nanoparticles (berberine-LCNs)-based treatment to human broncho-epithelial cells and macrophage inhibits oxidative stress, inflammation, and senescence induced by cigarette-smoke extract. The developed berberine-LCNs were found to have favourable physiochemical parameters, such as high entrapment efficiency and sustained in vitro release. The cellular-assay observations revealed that berberine-LCNs showed potent antioxidant activity by suppressing the generation of reactive oxygen species in both broncho-epithelial cells (16HBE) and macrophages (RAW264.7), and modulating the genes involved in inflammation and oxidative stress. Similarly, in 16HBE cells, berberine-LCNs inhibited the cigarette smoke-induced senescence as revealed by X-gal staining, gene expression of CDKN1A (p21), and immunofluorescent staining of p21. Further in-depth mechanistic investigations into antioxidative, anti-inflammatory, and antisenescence research will ersify the current findings of berberine as a promising therapeutic approach for inflammatory lung diseases caused by cigarette smoking.
Publisher: Elsevier BV
Date: 09-2022
Publisher: MDPI AG
Date: 18-10-2019
DOI: 10.3390/IJMS20205176
Abstract: Cigarette smoking causes lung inflammation and tissue damage. Lung fibroblasts play a major role in tissue repair. Previous studies have reported smoking-associated changes in fibroblast responses and methylation patterns. Our aim was to identify the effect of current smoking on miRNA expression in primary lung fibroblasts. Small RNA sequencing was performed on lung fibroblasts from nine current and six ex-smokers with normal lung function. MiR-335-5p and miR-335-3p were significantly downregulated in lung fibroblasts from current compared to ex-smokers (false discovery rate (FDR) .05). Differential miR-335-5p expression was validated with RT-qPCR (p-value = 0.01). The results were validated in lung tissue from current and ex-smokers and in bronchial biopsies from non-diseased smokers and never-smokers (p-value .05). The methylation pattern of the miR-335 host gene, determined by methylation-specific qPCR, did not differ between current and ex-smokers. To obtain insights into the genes regulated by miR-335-5p in fibroblasts, we overlapped all proven miR-335-5p targets with our previously published miRNA targetome data in lung fibroblasts. This revealed Rb1, CARF, and SGK3 as likely targets of miR-335-5p in lung fibroblasts. Our study indicates that miR-335-5p downregulation due to current smoking may affect its function in lung fibroblasts by targeting Rb1, CARF and SGK3.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.CBI.2020.108947
Abstract: Inflammatory responses play a remarkable role in the mechanisms of acute and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and lung cancer. Currently, there is a resurgence in the use of drugs from natural sources for various ailments as potent therapeutics. Berberine, an alkaloid prominent in the Chinese traditional system of medicine has been reported to exert therapeutic properties in various diseases. Nevertheless, the number of studies focusing on the curative potential of berberine in inflammatory diseases involving the respiratory system is limited. In this review, we have attempted to discuss the reported anti-inflammatory properties of berberine that function through several pathways such as, the NF-κB, ERK1/2 and p38 MAPK pathways which affect several pro-inflammatory cytokines in the pathophysiological processes involved in chronic respiratory diseases. This review would serve to provide valuable information to researchers who work in this field and a new direction in the field of drug discovery with respect to respiratory diseases.
Publisher: BMJ
Date: 02-2008
Abstract: Rhinovirus infection is responsible for considerable morbidity and mortality as the major cause of exacerbations of asthma, and is also known to induce exacerbations of cystic fibrosis and chronic obstructive pulmonary disease. Exacerbations of these diseases are also frequently associated with bacterial and atypical bacterial infection. Alveolar macrophages are the major immune cells in the airways and are important in defence against bacterial infections. The authors investigated whether rhinovirus modifies cytokine release, the pattern recognition receptor expression and phagocytosis by human alveolar macrophages in response to bacterial products. Viable rhinovirus was detected in macrophages up to 3 days after exposure and viral RNA expression persisted for 10 days. Infectious but not UV inactivated rhinovirus increased tumour necrosis factor α (TNFα) and interleukin (IL)8 release by macrophages. In contrast, infectious rhinovirus impaired lipopolysaccharide and lipoteichoic acid induced TNFα and IL8 secretion by macrophages. Rhinovirus induced impairment of macrophage antibacterial immune responses did not involve IL10, prostaglandin E 2 or downregulation of Toll-like receptor 2. Furthermore, the macrophage phagocytic response to labelled bacterial particles, but not to latex beads, was impaired. The authors have identified impairment of cytokine responses to bacterial lipopolysaccharide and lipoteichoic acid by alveolar macrophages in response to infectious rhinovirus. Virus induced impairment of antibacterial host defence has important implications in the pathogenesis of exacerbations of respiratory diseases.
Publisher: American Thoracic Society
Date: 06-2009
Publisher: Wiley
Date: 15-01-2004
DOI: 10.1002/MRD.20030
Abstract: Recent evidence indicates that mammalian gametogenesis and preimplantation development may be adversely affected by both assisted reproductive and stem cell technologies. Thus, a better understanding of the developmental regulation of the underlying epigenetic processes that include DNA methylation is required. We have, therefore, monitored the expression, by PCR, of the mRNAs of DNA methyltransferases (DNMTs), methyl-CpG-binding domain proteins (MBDs), and CpG binding protein (CGBP) in a developmental series of lified cDNA s les derived from staged human ovarian follicles, oocytes, preimplantation embryos, human embryonic stem (hES) cells and in similar murine cDNA s les. Transcripts of these genes were detected in human ovarian follicles (DNMT3A, DNMT3b1, DNMT3b4, DNMT1, MDBs1-4, MeCP2, CGBP), germinal vesicle (GV) oocytes (DNMT3A, DNMT3b1, DNMT1, MDBs1-4, MeCP2, CGBP), mature oocytes (DNMT3A, DNMT3b1, DNMT1, CGBP), and preimplantation embryos (DNMT3A, DNMT3b1, DNMT1, DNMT3L, MBD2, MDB4, CGBP). Differential expression of DNMT3B gene transcripts in undifferentiated (DNMT3b1) and in vitro differentiated human ES cells (DNMT3b3) further demonstrated an association of the DNMT3b1 transcript variant with totipotent and pluripotent human cells. Significantly, whilst the murine Dnmt3L gene is both expressed and essential for imprint establishment during murine oogenesis, transcripts of the human DNMT3L gene were only detected after fertilisation. Therefore, the mechanisms and/or the timing of imprint establishment may differ in humans.
Publisher: Public Library of Science (PLoS)
Date: 14-01-2014
DOI: 10.1371/ANNOTATION/D2BE9C62-8D74-4CFB-B49C-B900EA8CD17C
Publisher: MDPI AG
Date: 28-01-2023
Abstract: Tenascin C (TNC) is a multifunctional large extracellular matrix protein involved in numerous cellular processes in embryonic development and can be increased in disease, or under conditions of trauma or cell stress in adults. However, the role of TNC in lung diseases remains unclear. In this study, we investigated the expression of TNC during development, in offspring following maternal particulate matter (PM) exposure, asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. TNC expression is increased during lung development in biopsy cells, endothelial cells, mesenchymal cells, and epithelial cells. Maternal PM exposure increased TNC and collagen deposition, which was not affected by the removal of PM exposure after pregnancy. TNC expression was also increased in basal epithelial cells and fibroblasts in patients with asthma and AT2 and endothelial cells in patients with COPD. Furthermore, there was an increase in the expression of TNC in stage II compared to stage IA lung cancer however, overall survival analysis showed no correlation between levels of TNC and survival. In conclusion, TNC is increased during lung development, in offspring following maternal PM exposure, and in asthma, COPD, and lung cancer tissues. Therefore, targeting TNC may provide a novel therapeutic target for lung diseases.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Future Medicine Ltd
Date: 05-2022
Abstract: Pulmonary diseases such as lung cancer, asthma and tuberculosis have remained one of the common challenges globally. Polymeric micelles (PMs) have emerged as an effective technique for achieving targeted drug delivery for a local as well as a systemic effect. These PMs encapsulate and protect hydrophobic drugs, increase pulmonary targeting, decrease side effects and enhance drug efficacy through the inhalation route. In the current review, emphasis has been placed on the different barriers encountered by the drugs given via the pulmonary route and the mechanism of PMs in achieving drug targeting. The applications of PMs in different pulmonary diseases have also been discussed in detail.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2023
DOI: 10.1007/S00210-023-02603-5
Abstract: Lung cancer is the second most prevalent type of cancer and is responsible for the highest number of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) makes up the majority of lung cancer cases. Zerumbone (ZER) is natural compound commonly found in the roots of Zingiber zerumbet which has recently demonstrated anti-cancer activity in both in vitro and in vivo studies. Despite their medical benefits, ZER has low aqueous solubility, poor GI absorption and oral bioavailability that hinders its effectiveness. Liquid crystalline nanoparticles (LCNs) are novel drug delivery carrier that have tuneable characteristics to enhance and ease the delivery of bioactive compounds. This study aimed to formulate ZER-loaded LCNs and investigate their effectiveness against NSCLC in vitro using A549 lung cancer cells. ZER-LCNs, prepared in the study, inhibited the proliferation and migration of A549 cells. These inhibitory effects were superior to the effects of ZER alone at a concentration 10 times lower than that of free ZER, demonstrating a potent anti-cancer activity of ZER-LCNs. The underlying mechanisms of the anti-cancer effects by ZER-LCNs were associated with the transcriptional regulation of tumor suppressor genes P53 and PTEN , and metastasis-associated gene KRT18 . The protein array data showed downregulation of several proliferation associated proteins such as AXL, HER1, PGRN, and BIRC5 and metastasis-associated proteins such as DKK1, CAPG, CTSS, CTSB, CTSD, and PLAU. This study provides evidence of potential for increasing the potency and effectiveness of ZER with LCN formulation and developing ZER-LCNs as a treatment strategy for mitigation and treatment of NSCLC.
Publisher: American Thoracic Society
Date: 2016
Publisher: Wiley
Date: 12-2010
DOI: 10.1002/JCP.22295
Abstract: Human bronchial epithelial (HBE) cells contribute to asthmatic airway inflammation by secreting cytokines, chemokines, and growth factors, including interleukin (IL)-6, IL-8 and transforming growth factor (TGF) β1, all of which are elevated in asthmatic airways. This study examines the signaling pathways leading to TGFβ1 induced IL-6 and IL-8 in primary HBE cells from asthmatic and non-asthmatic volunteers. HBE cells were stimulated with TGFβ1 in the presence or absence of signaling inhibitors. IL-6 and IL-8 protein and mRNA were measured by ELISA and real-time PCR respectively, and cell signaling kinases by Western blot. TGFβ1 increased IL-6, but inhibited IL-8 production in both asthmatic and non-asthmatic cells however, TGF induced significantly more IL-6 in asthmatic cells. Inhibition of JNK MAP kinase partially reduced TGFβ1 induced IL-6 in both cell groups. TGFβ1 induced Smad2 phosphorylation, and blockade of Smad2/3 prevented both the TGFβ1 modulated IL-6 increase and the decrease in IL-8 production in asthmatic and non-asthmatic cells. Inhibition of Smad2/3 also increased basal IL-8 release in asthmatic cells but not in non-asthmatic cells. Using CHIP assays we demonstrated that activated Smad2 bound to the IL-6, but not the IL-8 promoter region. We conclude that the Smad2/3 pathway is the predominant TGFβ1 signaling pathway in HBE cells, and this is altered in asthmatic bronchial epithelial cells. Understanding the mechanism of aberrant pro-inflammatory cytokine production in asthmatic airways will allow the development of alternative ways to control airway inflammation.
Publisher: Springer Singapore
Date: 2019
Publisher: Elsevier BV
Date: 02-2021
Publisher: American Thoracic Society
Date: 15-03-2016
Publisher: AME Publishing Company
Date: 03-2019
Publisher: Frontiers Media SA
Date: 18-02-2022
DOI: 10.3389/FNCEL.2022.818536
Abstract: Hypoxic-ischemic encephalopathy affects ∼6 in 1,000 preterm neonates, leading to significant neurological sequela (e.g., cognitive deficits and cerebral palsy). Maternal smoke exposure (SE) is one of the common causes of neurological disorders however, female offspring seems to be less affected than males in our previous study. We also showed that maternal SE exaggerated neurological disorders caused by neonatal hypoxic-ischemic brain injury in adolescent male offspring. Here, we aimed to examine whether female littermates of these males are protected from such insult. BALB/c dams were exposed to cigarette smoke generated from 2 cigarettes twice daily for 6 weeks before mating, during gestation and lactation. To induce hypoxic-ischemic brain injury, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen) at postnatal day (P) 10. Behavioral tests were performed at P40–44, and brain tissues were collected at P45. Maternal SE worsened the defects in short-term memory and motor function in females with hypoxic-ischemic injury however, reduced anxiety due to injury was observed in the control offspring, but not the SE offspring. Both hypoxic-ischemic injury and maternal SE caused significant loss of neuronal cells and synaptic proteins, along with increased oxidative stress and inflammatory responses. Oxidative stress and inflammatory response due to maternal SE may be the mechanism of worsened neurological outcomes by hypoxic-ischemic brain injury in females, which was similar to their male littermates shown in our previous study.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2022
Publisher: European Respiratory Society
Date: 09-09-2023
Publisher: AME Publishing Company
Date: 03-2019
Publisher: AME Publishing Company
Date: 03-2019
Publisher: Public Library of Science (PLoS)
Date: 17-05-2011
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.BIOPHA.2018.11.051
Abstract: In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such ex le that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
Publisher: American Physiological Society
Date: 08-2012
DOI: 10.1152/AJPLUNG.00097.2012
Abstract: Eicosanoids are lipid-signaling mediators released by many cells in response to various stimuli. Increasing evidence suggests that eicosanoids such as leukotrienes and prostaglandins (PGs) may directly mediate remodeling. In this study, we assessed whether these substances could alter extracellular matrix (ECM) proteins and the inflammatory profiles of primary human airway smooth muscle cells (ASM) and fibroblasts. PGE 2 decreased both fibronectin and tenascin C in fibroblasts but only fibronectin in ASM. PGD 2 decreased both fibronectin and tenascin C in both ASM and fibroblasts, whereas PGF 2α had no effect on ECM deposition. The selective PGI 2 analog, MRE-269, decreased fibronectin but not tenascin C in both cell types. All the PGs increased IL-6 and IL-8 release in a dose-dependent manner in ASM and fibroblasts. Changes in ECM deposition and cytokine release induced by prostaglandins in both ASM and fibroblasts were independent of an effect on cell number. Neither the acute nor repeated stimulation with leukotrienes had an effect on the deposition of ECM proteins or cytokine release from ASM or fibroblasts. We concluded that, collectively, these results provide evidence that PGs may contribute to ECM remodeling to a greater extent than leukotrienes in airway cells.
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.
Publisher: American Physiological Society
Date: 02-2012
DOI: 10.1152/AJPLUNG.00163.2011
Abstract: β 2 -Adrenergic receptor (β2AR) agonists induce airway relaxation via cAMP. Phosphodiesterase (PDE)s degrade and regulate cAMP, and in airway smooth muscle (ASM) cells PDE4D degrades cAMP. Long-acting β 2 -agonists are now contraindicated as monotherapy for asthma, and increased PDE4D has been speculated to contribute to this phenomenon. In this study we investigated the expression of PDE4D in asthmatic and nonasthmatic ASM cells and its regulation by formoterol and budesonide. Primary ASM cells from people with or without asthma were stimulated with transforming growth factor (TGF)-β 1 , formoterol, and/or budesonide. PDE4D mRNA was assessed by real-time PCR, or PCR to assess splice variant production. PDE4D protein was assessed by Western blotting, and we investigated the effect of formoterol on cAMP production and PDE activity. Interleukin (IL)-6 was assessed using ELISA. PDE4D mRNA was dose dependently upregulated by formoterol, with a single splice variant, PDE4D5, present. Formoterol did not induce PDE4D protein at time points between 3 to 72 h, whereas it did induce and increase IL-6 secretion. We pretreated cells with actinomycin D and a proteasome inhibitor, MG132, and found no evidence of alterations in mRNA, protein expression, or degradation of PDE4D. Finally PDE activity was not altered by formoterol. This study shows, for the first time, that PDE4D5 is predominantly expressed in human ASM cells from people with and without asthma and that formoterol does not upregulate PDE4D protein production. This leads us to speculate that continual therapy with β2AR agonists is unlikely to cause PDE4-mediated tachyphylaxis.
Publisher: The Korean Academy of Asthma, Allergy and Clinical Immunology and The Korean Academy of Pediatric Al
Date: 2022
Publisher: Wiley
Date: 08-08-2019
DOI: 10.1111/RESP.13668
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease that has a poor 3-year median survival rate with unclear pathophysiology. Radiological features include bibasal, subpleural fibrosis and honeycombing while its pathology is characterized by fibroblastic foci and honeycombing. Proteomic analysis of circulating molecules in plasma may identify factors that characterize IPF and may assist in the diagnosis, prognostication and determination of pathogenic pathways in this condition. Two independent quantitative proteomic techniques were used, isobaric tags for relative and absolute quantitation (iTRAQ) and multiple reaction monitoring (MRM), to identify differentially expressed plasma proteins in a group of IPF patients in comparison to healthy controls with normal lung function matched for age and gender. Five proteins were identified to be differentially expressed in IPF compared to healthy controls (upregulation of platelet basic protein and downregulation of actin, cytoplasmic 2, antithrombin-III, extracellular matrix protein-1 and fibronectin). This study further validates the combinational use of non-targeted discovery proteomics (iTRAQ) with targeted quantitation by mass spectrometry (MRM) of soluble biomarkers to identify potentially important molecules and pathways for pulmonary diseases such as IPF.
Publisher: Future Medicine Ltd
Date: 10-2022
Abstract: The prevalence of lung diseases is increasing year by year and existing drug therapies only provide symptomatic relief rather than targeting the actual cause. Nucleic acids can be used as an alternative therapeutic approach owing to their potential to reform a homeostatic balance by upregulating protective genes or downregulating damaging genes. However, their inherent properties, such as poor stability, ineffective cellular uptake, negative charge and so on, hinder their clinical utility. Such limitations can be overcome by exploiting the functional chemistry of polymeric micelles (PMs) for site-specific delivery, transfection efficiency and improved stability. With this objective, the present work describes the advancements made in designing nucleic acid-based PMs for treating lung diseases followed by approaches requiring consideration for clinical applications.
Publisher: Stichting Nase
Date: 09-2017
DOI: 10.4193/RHINO16.215
Abstract: Background: Although extracellular matrix (ECM) proteins are associated with irreversible lower airway changes, the relationship with upper airway remodelling which occurs during chronic rhinosinusitis (CRS) is poorly understood. This study assessed the expression of ECM proteins periostin, fibulin-1, fibronectin and collagenIV in nasal mucosa of patients with and without histologic features of remodelling. Methods: A cross-sectional study of sinonasal mucosal biopsies taken from patients, undergoing surgery for CRS was performed, where patients were grouped according to remodelling, defined by basement membrane thickening (BMT over 7.5 micrometer) and subepithelial fibrosis. An overall view and three random fields of immunostained tissue sections that included epithelium, basement membrane and submucosa, were imaged using Zeiss Zen software. The area and intensity of positive staining were scored by two blinded observers, using a 12-point ordinal scale of weak to strong. Results: 65 patients (47.6 +/- 13.4years, 44.6% female) were assessed. Patients were grouped as controls 26.2%, BMT/no fibrosis 38.5% or BMT and fibrosis 33.8%. Stronger grade of periostin expression was associated with remodelling changes and tissue eosinophilia over 10/HPF. Fibulin-1, fibronectin and collagenIV did not differ. Conclusion: Periostin expression was associated with the presence of BMT, fibrosis and tissue eosinophilia and may identify patients undergoing remodelling changes.
Publisher: Frontiers Media SA
Date: 26-09-2017
Publisher: European Respiratory Society (ERS)
Date: 11-2021
Publisher: Elsevier BV
Date: 02-2011
Publisher: Informa UK Limited
Date: 12-05-2021
DOI: 10.1080/10408398.2021.1915744
Abstract: Respiratory diseases, both acute and chronic, are reported to be the leading cause of morbidity and mortality, affecting millions of people globally, leading to high socio-economic burden for the society in the recent decades. Chronic inflammation and decline in lung function are the common symptoms of respiratory diseases. The current treatment strategies revolve around using appropriate anti-inflammatory agents and bronchodilators. A range of anti-inflammatory agents and bronchodilators are currently available in the market however, the usage of such medications is limited due to the potential for various adverse effects. To cope with this issue, researchers have been exploring various novel, alternative therapeutic strategies that are safe and effective to treat respiratory diseases. Several studies have been reported on the possible links between food and food-derived products in combating various chronic inflammatory diseases. Nutraceuticals are ex les of such food-derived products which are gaining much interest in terms of its usage for the well-being and better human health. As a consequence, intensive research is currently aimed at identifying novel nutraceuticals, and there is an emerging notion that nutraceuticals can have a positive impact in various respiratory diseases. In this review, we discuss the efficacy of nutraceuticals in altering the various cellular and molecular mechanisms involved in mitigating the symptoms of respiratory diseases.
Publisher: American Physiological Society
Date: 06-2022
Abstract: The COVID-19 pandemic has been a strong driver for moving more teaching and learning activities online. Border restrictions have had a severe impact on international students either hoping to enroll in courses offered in Australia or continue with such courses if they are already enrolled. The online learning experience is likely different between students onshore and offshore. This study took a unique opportunity to investigate any such differences in students’ attitudes toward remote learning, necessitated by the pandemic, by comparing two cohorts of students, Australia versus China based. An anonymous survey using the Likert Scale and open-ended questions was available for student feedback on subject delivery. The students based in Australia expressed a preference for remote learning due to the convenience of attendance and availability of the video recordings. However, students in China had a strong preference for face-to-face sessions, with the lack of prior experience in an English-speaking learning environment and hesitance to speak with the lecturers and engage in the learning activities possible reasons for this. In quizzes, students in Australia performed better than those in China regardless of local or international student status. This difference may be due to the Australian-based students’ prior experience of English-speaking environments and open-book quizzes. In conclusion, remote learning in a familiar language and learning environment is accepted by students, whereas if the teaching is delivered in a second language using unfamiliar teaching methods, remote learning will require additional scaffolding to enhance their learning experience.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-11-2021
Publisher: European Respiratory Society (ERS)
Date: 10-2005
DOI: 10.1183/09031936.05.00016905
Abstract: Lymphangioleiomyomatosis (LAM) is associated with abnormal airway smooth muscle that leads to the characteristic pathology of lung nodule formation and destruction of lung tissue. The current authors have previously identified abnormal behaviour of airway smooth muscle cells from patients with asthma. In this study, cells and tissue sections derived from patients with LAM (n=7), asthma (n=8), and nonasthmatic controls (n=9) were compared. The presence of the antigen human melanosome (HM)B-45 was investigated, along with the proliferation and release of extracellular matrix proteins, release of endogenous prostaglandin E2 (PGE2), vascular endothelial growth factor and connective tissue growth factor, and the expression of integrins. Positive HMB-45 staining was found in all LAM patients and no controls. Proliferation of LAM cells was not different from control cells nor was its inhibition by beta-agonists, corticosteroids, rapamycin or PGE2. However, endogenous PGE2 levels were markedly decreased in LAM cells, and this was associated with decreased expression of the inducible form of cyclooxygenase (COX-2). The increased levels of connective tissue growth factor seen in asthma cells were not observed in LAM. Elastin mRNA in response to transforming growth factor-beta stimulation was markedly lower in LAM cells than either asthma or control cells. In conclusion, lymphangioleiomyomatosis cells exhibit abnormal properties in vitro that may contribute to pathophysiology and symptomatology in patients with lymphangioleiomyomatosis.
Publisher: MDPI AG
Date: 14-07-2023
DOI: 10.3390/NU15143140
Abstract: High-fat diet (HFD) consumption and tobacco smoking are risk factors for chronic kidney disease. E-cigarettes have gained significant popularity among younger populations worldwide, especially among overweight in iduals. It is unclear whether vaping interacts with HFD consumption to impact renal health. In this study, Balb/c mice (male, 7 weeks old) were fed a pellet HFD (43% fat, 20 kJ/g) for 16 weeks when exposed to nicotine or nicotine-free e-vapour from weeks 11 to 16. While HFD alone increased collagen Ia and IV depositions, it did not cause significant oxidative stress and inflammatory responses in the kidney itself. On the other hand, e-vapour exposure alone increased oxidative stress and damaged DNA and mitochondrial oxidative phosphorylation complexes without significant impact on fibrotic markers. However, the combination of nicotine e-vapour and HFD increased inflammatory responses, oxidative stress-induced DNA injury, and pro-fibrotic markers, suggesting accelerated development of renal pathology. Nicotine-free e-vapour exposure and HFD consumption suppressed the production of mitochondrial OXPHOS complexes and extracellular matrix protein deposition, which may cause structural instability that can interrupt normal kidney function in the future. In conclusion, our study demonstrated that a HFD combined with e-cigarette vapour exposure, especially when containing nicotine, can increase susceptibility to kidney disease.
Publisher: MDPI AG
Date: 21-07-2019
DOI: 10.3390/NU11071669
Abstract: Maternal smoking leads to glucose and lipid metabolic disorders and hepatic damage in the offspring, potentially due to mitochondrial oxidative stress. Mitoquinone mesylate (MitoQ) is a mitochondrial targeted antioxidant with high bioavailability. This study aimed to examine the impact of maternal cigarette smoke exposure (SE) on offspring’s metabolic profile and hepatic damage, and whether maternal MitoQ supplementation during gestation can affect these changes. Female Balb/c mice (eight weeks) were either exposed to air or SE for six weeks prior to mating and throughout gestation and lactation. A subset of the SE dams were supplied with MitoQ in the drinking water (500 µmol/L) during gestation and lactation. Intraperitoneal glucose tolerance test was performed in the male offspring at 12 weeks and the livers and plasma were collected at 13 weeks. Maternal SE induced glucose intolerance, hepatic steatosis, mitochondrial oxidative stress and related damage in the adult offspring. Maternal MitoQ supplementation reduced hepatic mitochondrial oxidative stress and improved markers of mitophagy and mitochondrial biogenesis. This may restore hepatic mitochondrial health and was associated with an amelioration of glucose intolerance, hepatic steatosis and pathological changes induced by maternal SE. MitoQ supplementation may potentially prevent metabolic dysfunction and hepatic pathology induced by intrauterine SE.
Publisher: American Physiological Society
Date: 08-2009
DOI: 10.1152/AJPLUNG.90624.2008
Abstract: The antipsoriatic dimethylfumarate (DMF) has been anecdotically reported to reduce asthma symptoms and to improve quality of life of asthma patients. DMF decreases the expression of proinflammatory mediators by inhibiting the transcription factor NF-κB and might therefore be of interest for the therapy of inflammatory lung diseases. In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNFα-induced asthma-relevant cytokines and NF-κB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1–100 μM) and/or dexamethasone (0.0001–0.1 μM), NF-κB p65 siRNA (100 nM), the NF-κB inhibitor helenalin (1 μM) before stimulation with PDGF-BB or TNFα (10 ng/ml). Cytokine release was measured by ELISA. NF-κB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFα-induced eotaxin, RANTES, and IL-6 as well as PDGF-BB-induced IL-6 expression was inhibited by DMF and by dexamethasone from asthmatic and nonasthmatic ASMC, but the combination of both drugs showed no glucocorticoid sparing effect in either of the two groups. NF-κB p65 siRNA and/or the NF-κB inhibitor helenalin reduced PDGF-BB- and TNFα-induced cytokine expression, suggesting the involvement of NF-κB signaling. DMF inhibited TNFα-induced NF-κB p65 phosphorylation, NF-κB nuclear entry, and NF-κB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-κB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-κB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-κB but a wider range of NF-κB-linked signaling proteins, which may explain its potential beneficial effect in asthma.
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.CBI.2022.110138
Abstract: Bronchial asthma is a chronic lung disorder, that affects an estimated 262 million people worldwide, thereby, causing a large socio-economic burden. Drug molecules from natural sources have exhibited a good promise in providing an alternative therapy in many chronic ailments. Solasodine, a glycoalkaloid has received an immense interest due to its large pharmacological and industrial value, however, its usefulness in asthma control has not been investigated till date. In this work, solasodine was tested for its ability to reverse several characteristics of bronchial asthma induced by intraperitoneal injection of ovalbumin (OVA) and aluminium hydroxide in experimental rats. Treating asthmatic animals with solasodine (1 mg/kg b.w. or 10 mg/kg b.w.) or dexamethasone (2.5 mg/kg b.w.) reversed OVA-induced airway hyperresponsiveness, infiltration of inflammatory cells and histamine levels in the airways. Furthermore, as compared to OVA-control rats, allergen-induced elevated levels of IgE, nitrites, nitric oxide, and pro-inflammatory mediators, including TNF-α, IL-1β, LTD-4, and Th2-cytokines, particularly, IL-4, IL-5 were remarkably reduced in both bronchoalveolar lavage fluid and blood. These findings are supported by significant protection offered by various treatments against OVA-induced airway inflammation and mast cell degranulation in mesenteric tissues. Further, In-silico molecular docking studies performed to determine inhibitory potential of solasodine at IL-4 and IL-5, demonstrated strong affinity of phytocompound for these receptors than observed with antagonists previously reported. Results of current study imply that solasodine has therapeutic promise in allergic asthma, presumably due to its ability to prevent mast cell degranulation and consequent generation of histamine and Th2-associated cytokines in airways.
Publisher: Elsevier BV
Date: 03-2013
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.RMED.2022.106935
Abstract: Identification of eosinophilic asthma (EA) using sputum analysis is important for disease monitoring and in idualized treatment. But it is laborious and technically demanding. We aimed to develop and validate an effective model to predict EA with multidimensional assessment (MDA). The asthma patients who underwent a successful sputum induction cytological analysis were consecutively recruited from March 2014 to January 2021. The variables assessed by MDA were screened by least absolute shrinkage and selection operator (LASSO) and logistic regression to develop a nomogram and an online web calculator. Validation was performed internally by a bootstrap s ling method and externally in the validation cohort. Diagnostic accuracy of the model in different asthma subgroups were also investigated. In total of 304 patients in the training cohort and 95 patients in the validation cohort were enrolled. Five variables were identified in the EA prediction model: gender, nasal polyp, blood eosinophils, blood basophils and FeNO. The C-index of the model was 0.86 (95% CI: 0.81-0.90) in the training cohort and 0.84 (95% CI: 0.72-0.89) in the validation cohort. The calibration curve showed good agreement between the prediction and actual observation. The decision curve analysis (DCA) also demonstrated that the EA prediction model was clinically beneficial. An online publicly available web calculator was constructed (asthmaresearcherlimin.shinyapps.io/DynNomapp/). We developed and validated a multivariable model based on MDA to help the diagnosis of EA, which has good diagnostic performance and clinical practicability. This practical tool may be a useful alternative for predicting EA in the clinic.
Publisher: American Society for Clinical Investigation
Date: 06-2022
DOI: 10.1172/JCI160595
Publisher: Springer Science and Business Media LLC
Date: 10-12-2022
DOI: 10.1038/S41467-022-35253-X
Abstract: Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation and infective exacerbations, however, in-vitro model systems for the study of host-pathogen interaction at the in idual level are lacking. Here, we describe the establishment of nasopharyngeal and bronchial organoids from healthy in iduals and COPD that recapitulate disease at the in idual level. In contrast to healthy organoids, goblet cell hyperplasia and reduced ciliary beat frequency were observed in COPD organoids, hallmark features of the disease. Single-cell transcriptomics uncovered evidence for altered cellular differentiation trajectories in COPD organoids. SARS-CoV-2 infection of COPD organoids revealed more productive replication in bronchi, the key site of infection in severe COVID-19. Viral and bacterial exposure of organoids induced greater pro-inflammatory responses in COPD organoids. In summary, we present an organoid model that recapitulates the in vivo physiological lung microenvironment at the in idual level and is amenable to the study of host-pathogen interaction and emerging infectious disease.
Publisher: Wiley
Date: 08-11-2020
DOI: 10.1111/RESP.13972
Publisher: Elsevier BV
Date: 08-2022
Publisher: American Physiological Society
Date: 02-2012
DOI: 10.1152/AJPLUNG.00453.2010
Abstract: Chronic obstructive pulmonary disease (COPD) and asthma are characterized by irreversible remodeling of the airway walls, including thickening of the airway smooth muscle layer. Perlecan is a large, multidomain, proteoglycan that is expressed in the lungs, and in other organ systems, and has been described to have a role in cell adhesion, angiogenesis, and proliferation. This study aimed to investigate functional properties of the different perlecan domains in relation to airway smooth muscle cells (ASMC). Primary human ASMC obtained from donors with asthma ( n = 13), COPD ( n = 12), or other lung disease ( n = 20) were stimulated in vitro with 1 ng/ml transforming growth factor-β 1 (TGF-β 1 ) before perlecan deposition and cytokine release were analyzed. In some experiments, inhibitors of signaling molecules were added. Perlecan domains I–V were seeded on tissue culture plates at 10 μg/ml with 1 μg/ml collagen I as a control. ASM was incubated on top of the peptides before being analyzed for attachment, proliferation, and wound healing. TGF-β 1 upregulated deposition of perlecan by ASMC from COPD subjects only. TGF-β 1 upregulated release of IL-6 into the supernatant of ASMC from all subjects. Inhibitors of SMAD and JNK signaling molecules decreased TGF-β 1 -induced perlecan deposition by COPD ASMC. Attachment of COPD ASMC was upregulated by collagen I and perlecan domains IV and V, while perlecan domain II upregulated attachment only of asthmatic ASMC. Seeding on perlecan domains did not increase proliferation of any ASMC type. TGF-β 1 -induced perlecan deposition may enhance attachment of migrating ASMC in vivo and thus may be a mechanism for ASMC layer hypertrophy in COPD.
Publisher: Oxford University Press (OUP)
Date: 21-02-2017
DOI: 10.1093/NAR/GKX116
Publisher: Research Square Platform LLC
Date: 04-03-2020
Abstract: Background: Cigarette smoke exposure ( SE ) during pregnancy is the largest modifiable risk factor for the development of lung disorders in offspring. We have previously shown that maternal L-Carnitine treatment can reduce the adverse impacts of maternal SE on renal and brain disorders in offspring. Here, we investigated the effect of maternal L-Carnitine supplementation on lung inflammatory pathways, autophagy, and mitophagy markers in the offspring in response to maternal SE. Female Balb/c mice (8 weeks) were exposed to cigarette smoke for 6 weeks prior to mating, during gestation and lactation. Half of the SE mothers were given L-Carnitine supplementation (1.5mM in drinking water, SE+LC) during gestation and lactation. Lungs from the offspring were studied at birth and adulthood (13 weeks) in both genders. Results: At birth, in male offspring, there were increased lev inflammatory markers (phosphorylated(p)-ERK1,2, p-P38 MAPK, p-NF-kB), and inflammasome marker (NLRP3), as well as mitophagy fission marker Drp-1 and autophagosome marker (LC3A/B-II) in the lung. Maternal L-Carnitine supplementation significantly reduced NLRP3 level. In contrast, maternal SE only increased IL1-β in female offspring, which was reversed by maternal L-Carnitine supplementation. At 13 weeks, there was an increase in LC3A/B-II and p-NF-kB in the male SE offspring with reduced p-JNK1,2, which were partially normalised by maternal L-Carnitine treatment. Female offspring were not affected by maternal SE at this age. Conclusion : Maternal SE had adverse impacts on the male offspring’s lung, which were partially alleviated by maternal L-Carnitine supplementation. Females seem to be protected from the adverse effects of maternal SE.
Publisher: Wiley
Date: 17-11-2017
DOI: 10.1002/PATH.4979
Abstract: Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c
Publisher: Research Square Platform LLC
Date: 19-12-2019
Abstract: Background: Cigarette smoke exposure ( SE ) during pregnancy is the largest modifiable risk factor for the development of lung disorders in offspring. We have previously shown that maternal L-Carnitine treatment can reduce the adverse impacts of maternal SE on renal and brain disorders in offspring. Here, we investigated the effect of maternal L-Carnitine supplementation on lung inflammatory pathways, autophagy, and mitophagy markers in the offspring in response to maternal SE. Female Balb/c mice (8 weeks) were exposed to cigarette smoke for 6 weeks prior to mating, during gestation and lactation. Half of the SE mothers were given L-Carnitine supplementation (1.5mM in drinking water, SE+LC) during gestation and lactation. Lungs from the offspring were studied at birth and adulthood (13 weeks) in both genders. Results: At birth, in male offspring, there were increased lev inflammatory markers (phosphorylated(p)-ERK1,2, p-P38 MAPK, p-NF-kB), and inflammasome marker (NLRP3), as well as mitophagy fission marker Drp-1 and autophagosome marker (LC3A/B-II) in the lung. Maternal L-Carnitine supplementation significantly reduced NLRP3 level. In contrast, maternal SE only increased IL1-β in female offspring, which was reversed by maternal L-Carnitine supplementation. At 13 weeks, there was an increase in LC3A/B-II and p-NF-kB in the male SE offspring with reduced p-JNK1,2, which were partially normalised by maternal L-Carnitine treatment. Female offspring were not affected by maternal SE at this age. Conclusion: Maternal SE had adverse impacts on the male offspring’s lung, which were partially alleviated by maternal L-Carnitine supplementation. Females seem to be protected from the adverse effects of maternal SE.
Publisher: American Thoracic Society
Date: 10-2021
Publisher: European Respiratory Society
Date: 09-09-2023
Publisher: Wiley
Date: 04-03-2018
Abstract: Sex differences in disease susceptibility due to maternal programming have been reported. We previously observed that maternal smoking induced renal disease and neurological changes are restricted to males, while both male and female offspring develop metabolic disorders. We have also found that maternal L-carnitine supplementation during gestation and lactation can significantly improve glucose intolerance and hyperlipidaemia in male offspring. This study aimed to determine whether such beneficial effects can also occur in female offspring. Balb/c female mice were exposed to cigarette smoke (SE) 6 weeks prior to gestation, during gestation and lactation. A subgroup of the SE dams was given L-carnitine (1.5 mmol/L in drinking water) during gestation and lactation. Female offspring were studied at 20 days (weaning) and 13 weeks (adulthood). Maternal smoking increased liver weight (%) and blood glucose levels at 20 days, as well as glucose intolerance and plasma triglycerides levels at adulthood (P < .05). The hepatic lipid metabolic marker adipose triglyceride lipase was downregulated in the SE offspring at 20 days (P < .05). At 13 weeks, the hepatic pro-inflammatory markers IL-1β and TNF-α mRNA expression were upregulated, while the anti-inflammatory marker IL-10 mRNA expression was downregulated in the SE offspring (P < .05). Liver fibrosis was apparent at 20 days and 13 weeks. Maternal L-carnitine supplementation either normalised or suppressed the detrimental effects induced by maternal smoke exposure (P < .05). We conclude that maternal L-carnitine supplementation improves metabolic parameters in the female offspring of SE dams.
Publisher: Hindawi Limited
Date: 15-06-2021
DOI: 10.1155/2021/6613798
Abstract: Background. Eight-Constitution Medicine (ECM), an extension of Traditional Korean Medicine, ides the population into eight groups based on their physiological characteristics. ECM ides these eight groups into two larger groups based on autonomic reactivity: the Sympathicotonic group and the Vagotonic group (herein referred to as the Disympathetic Dimension). Heart Rate Variability (HRV) is a widely used biomedical tool to assess cardiac autonomic function. This raises the question of the utility of using HRV to correctly diagnose ECM constitutions. Methods. A systematic literature review was conducted to evaluate the correlation between HRV and constitutions in Korean Constitutional Medicine, including Eight-Constitution Medicine (ECM) and Sasang Constitution Medicine (SCM). The articles were obtained from both English (Scopus, PubMed, EMBASE, ProQuest, and Medline) and Korean databases (NDSL and RISS), in addition to Google Scholar, without date restriction. 20 studies met the inclusion criteria, and data were extracted against three aspects: (1) correlation between HRV and constitution, (2) HRV reporting and interpretation, and (3) extraneous factors that were controlled in the studies. Results. 386 articles were initially identified, which was reduced to n = 20 studies which met the inclusion criteria. Of these, 19 were SCM studies and 1 was an ECM study. S le sizes varied from 10 to 8498 men and women, with an age range of 10–80 years. SCM studies explored HRV differences by constitution, measuring HRV at resting, with controlled breathing, before and after acupuncture stimulation, and by other interventions. SCM studies reported either no significant differences (HRV at resting or with controlled breathing studies) or conflicting data (HRV with acupuncture stimulation studies). The single ECM study measured HRV at resting and after acupuncture stimulation but reported no significant differences between the two groups of Sympathicotonia and Vagotonia. Conclusions. Due to inconsistencies in study design, study population, and measures of HRV, there was no consistency in the data to support the use of HRV as a biomedical determinant of ECM constitutions.
Publisher: Elsevier BV
Date: 04-2023
Publisher: MDPI AG
Date: 12-2017
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.CBI.2022.110048
Abstract: Mucus gel constitutes of heavily cross-linked mucin fibers forming a viscoelastic, dense porous network that coats all the exposed epithelia not covered with the skin. The layer provides protection to the underlying gastrointestinal, respiratory, and female reproductive tracts, in addition to the organs such as the surface of eye by trapping the pathogens, irritants, environmental fine particles, and potentially hazardous foreign matter. However, this property of mucus gel poses a substantial challenge for realizing the localized and sustained drug delivery across the mucosal surfaces. The mucus permeating particles that spare the protective properties of mucus gel improve the therapeutic potency of the drugs aimed at the management of diseases, including sexually transmitted infections, lung cancer, irritable bowel disease, degenerative eye diseases and infections, and cystic fibrosis. As such, the mucoadhesive materials conjugated with drug molecules display a prolonged retention time in the mucosal gel that imparts a sustained release of the deliberated drug molecules across the mucosa. The contemporarily developed mucus penetrating materials for drug delivery applications comprise of a finer size, appreciable hydrophilicity, and a neutral surface to escape the entrapment within the cross-inked mucus fibers. Pertaining to the mucus secretion as a first line of defence in respiratory tract in response to the invading physical, chemical, and biological pathogens, the development of mucus penetrating materials hold promise as a stalwart approach for revolutionizing the respiratory drug delivery paradigm. The present review provides an epigrammatic collation of the mucus penetrating/mucoadhesive materials for achieving a controlled/sustained release of the cargo pharmaceutics and drug molecules across the respiratory mucus barrier.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Oxford University Press (OUP)
Date: 12-2002
Abstract: The Factor In the Germline alpha (FIGalpha) transcription factor regulates expression of the zona pellucida proteins ZP1, ZP2 and ZP3 and is essential for folliculogenesis in the mouse. Using the published mouse Figla sequence, BLAST searches identified a human chromosome 2 BAC clone with high sequence identity. Using PCR primers derived from this clone, licons derived from ovarian follicles and mature oocytes revealed 100% identity with the appropriate human BAC clone, the expected homology with the mouse Figla gene sequence, and homology on translation with the FIGalpha protein identified in the Japanese rice fish, medaka (Oryzias latipes). PCR expression profiling of this transcript revealed FIGLA mRNA expression in cDNA derived from ovarian follicles (5/5 s les from the primordial through to the secondary stage) mature oocytes (6/9 s les), and less frequently in preimplantation embryos (2/7 s les). Subsequent BLAST searches revealed the predicted full length coding sequence of the human FIGalpha protein which demonstrates 68 and 25% similarity overall to mouse and medaka proteins respectively, with 96 and 57% identity respectively within the basic helix-loop-helix region. This confirms our identification of the human homologue for this gene which maps to chromosome 2p12. Further work is required to understand its role in normal human oocyte development and the potential involvement in human infertility.
Publisher: Elsevier BV
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 11-09-2014
DOI: 10.1186/S40247-014-0011-6
Abstract: Respiratory viral infections are the most common trigger of acute exacerbations in patients with allergic asthma. The anti-viral response of airway epithelial cells (AEC) may be impaired in asthmatics, while cytokines produced by AEC may drive the inflammatory response. We investigated whether AEC cultured in the presence of Th2 cytokines associated with an allergic environment exhibited altered responses to double-stranded RNA, a virus-like stimulus. We undertook preliminary studies using the MLE-12 cell line derived from mouse distal respiratory epithelial cells, then confirmed and extended our findings using low-passage human AEC. Cells were cultured in the absence or presence of the Th2 cytokines IL-4 and IL-13 for 48 hours, then stimulated with poly I:C for 4 hours. Expression of relevant anti-viral response and cytokine genes was assessed by quantitative real-time PCR. Secretion of cytokine proteins was assessed by immunoassay. Following stimulation with poly I:C, MLE-12 cells pre-treated with Th2 cytokines exhibited significantly higher levels of expression of mRNA for the cytokine genes Cxcl10 and Cxcl11 , as well as a trend towards increased expression of Cxcl9 and Il6. Expression of anti-viral response genes was mostly unchanged, although Stat1, Ifit1 and Ifitm3 were significantly increased in Th2 cytokine pre-treated cells. Human AEC pre-treated with IL-4 and IL-13, then stimulated with poly I:C, similarly exhibited significantly higher expression of IL8, CXCL9, CXCL10, CXCL11 and CCL5 genes. In parallel, there was significantly increased secretion of CXCL8 and CCL5, as well as a trend towards increased secretion of CXCL10 and IL-6. Again, expression of anti-viral response genes was not decreased. Rather, there was significantly enhanced expression of mRNA for type III interferons, RNA helicases and other interferon-stimulated genes. The Th2 cytokine environment appears to promote increased production of pro-inflammatory chemokines by AEC in response to double-stranded RNA, which could help explain the exaggerated inflammatory response to respiratory viral infection in allergic asthmatics. However, any impairment of anti-viral host defences in asthmatics appears unlikely to be a consequence of Th2 cytokine-induced downregulation of the expression of viral response genes by AEC.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.CHEMOSPHERE.2021.133082
Abstract: Traffic-related air pollution (TRAP) is global concern due to both the ecological damage of TRAP and the adverse health effects in Humans. Several strategies to reduce TRAP have been implemented, including the use of sustainable fuels, after-treatment technologies, and new energy vehicles. Such approaches can reduce the exhaust of particulate matter, adsorbed chemicals and a range of gases, but from a health perspective these approaches are not always successful. This review aims to discuss the approaches taken, and to then describe the likely health effects of these changes.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.NEULET.2018.07.001
Abstract: Maternal smoking can lead to perturbations in central metabolic regulators such as neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) signalling components in offspring. With the growing interest in e-cigarettes as a tobacco replacement, this short report assessed central metabolic regulation in offspring of mouse dams exposed to e-cigarettes. We examined the impact of continuous use of e-cigarettes, and e-cigarette replacement of tobacco cigarettes during pregnancy. Supplementation of an antioxidant l-carnitine was also co-used with tobacco cigarette in the mother to determine whether the impact of maternal tobacco smoking was oxidative stress driven. Balb/c mice were exposed to either nicotine-containing (E-cig18) or nicotine-free (E-cig0) e-cigarette aerosols or tobacco smoke (SE) prior to mating and until their pups were weaned. After mating, two SE sub-groups were changed to E-cig18 exposure (Replacement), or supplementation l-carnitine while SE was continued. Male offspring were studied at weaning age. The offspring of E-cig0 dams were the heaviest with the most body fat. Replacing SE with E-cig18 during pregnancy resulted in offspring with significantly less body fat. E-cig0 offspring had significantly increased mRNA expression of brain NPY and iNOS. Maternal SE upregulated mRNA expression of NPY, NPY Y1 receptor, POMC downstream components, and iNOS expression, which were normalised in Replacement offspring, but only partially normalised with maternal L-carnitine supplementation during gestation and lactation. Maternal exposure to either tobacco and nicotine-free e-cigarettes lead to disturbances in the level of central homeostatic control markers in offspring, suggesting that maternal exposure to e-cigarettes is not without risks.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.CBI.2022.109842
Abstract: Nutraceuticals are dietary supplements that are used to improve health, postpone aging, prevent illnesses, and maintain the human body's correct functioning. Nutraceuticals are now garnering a lot of interest because of their nutritional and therapeutic benefits. The research indicating the relevance of nutraceuticals as a possible therapeutic candidate against inflammatory lung disease was covered in this review. Nowadays, inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, asthma, pneumonia, lung cancer, becoming highly dreadful because of their associated fatality. Inflammation is one of the cores and common factors of these diseases which is mainly associated with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, NF-κB p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation, and initiation of the signaling pathway of the NF-κB. The secondary metabolites from natural sources are the active component that attenuates NF-κB and the associated pathway that inhibits inflammation in lung diseases. Nutraceuticals belonging to the chemical category polyphenols, alkaloids, terpenoids, flavonoids, tannins have the potential to combat the NF-κB pathway. Accordingly, this review discusses the medical value of nutraceuticals briefly and their ability to mitigate various inflammatory lung diseases through targeting inhibition of NF-κB.
Publisher: Wiley
Date: 18-04-2008
Publisher: Informa UK Limited
Date: 06-10-2021
Publisher: Bentham Science Publishers Ltd.
Date: 02-12-2020
DOI: 10.2174/1871530320666200503053846
Abstract: The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its erse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
Publisher: American Chemical Society (ACS)
Date: 06-07-2015
DOI: 10.1021/ACS.MOLPHARMACEUT.5B00124
Abstract: The aim of this study was to investigate the changes in transport and effectiveness of salbutamol sulfate (SAL) and budesonide (BD) following stimulation with transforming growth factor-β (TGF-β) in mono- and coculture models of bronchial and alveolar epithelium. Primary bronchial and alveolar epithelial cells, grown at air interface on filters, either as monocultures or in coculture with airway smooth muscle cells or alveolar macrophages, respectively, were stimulated with TGF-β. The biological response was modulated by depositing aerosolized SAL and BD on bronchial and alveolar models, respectively. Barrier integrity, permeability to fluorescein-Na, transport of the deposited drug, and the pharmacological response to SAL (cAMP and IL-8 levels) or BD (IL-6 and -8 levels) were measured. While stimulation with TGF-β did not have any significant effect on the transepithelial electrical resistance and permeability to fluorescein-Na in mono- and coculture models, transport of SAL and BD were affected in cultures from some of the patients (6 out of 12 for bronchial and 2 out of 4 for alveolar cells). The bronchial coculture showed a better responsiveness to SAL in terms of cAMP release than the monoculture. In contrast, the difference between alveolar mono- and cocultures to TGF-β mediated interleukin release and its modulation by BD was less pronounced. Our data point to intrinsic differences in the transport of, and responsiveness to, SAL and BD when epithelial cell cultures originate from different patients. Moreover, if the biological responses (e.g., IL-8, cAMP) involve communication between different cell types, coculture models are more relevant to measure such effects than monocultures.
Publisher: Public Library of Science (PLoS)
Date: 20-10-2017
Publisher: Springer Science and Business Media LLC
Date: 03-11-2018
Publisher: American Physiological Society
Date: 12-06-2019
DOI: 10.1152/AJPLUNG.00356.2012
Abstract: In asthma, airway smooth muscle (ASM) chemokine (C-X-C motif) receptor 3 (CXCR3) ligand production may attract mast cells or T lymphocytes to the ASM, where they can modulate ASM functions. In ASM cells (ASMCs) from people with or without asthma, we aimed to investigate JAK-STAT1, JNK, and Ca 2+ involvement in chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11 production stimulated by interferon-γ, IL-1β, and TNF-α combined (cytomix). Confluent, growth-arrested ASMC were treated with inhibitors for pan-JAK (pyridone-6), JAK2 (AG-490), JNK (SP-600125), or the sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA) pump (thapsigargin), Ca 2+ chelator (BAPTA-AM), or vehicle before and during cytomix stimulation for up to 24 h. Signaling protein activation as well as CXCL10/CXCL11 mRNA and protein production were examined using immunoblot analysis, real-time PCR, and ELISA, respectively. Cytomix-induced STAT1 activation was lower and CXCR3 ligand mRNA production was more sensitive to pyridone-6 and AG-490 in asthmatic than nonasthmatic ASMCs, but CXCL10/CXCL11 release was inhibited by the same proportion. Neither agent caused additional inhibition of release when used in combination with the JNK inhibitor SP-600125. Conversely, p65 NF-κB activation was higher in asthmatic than nonasthmatic ASMCs. BAPTA-AM abolished early CXCL10/CXCL11 mRNA production, whereas thapsigargin reduced it in asthmatic cells and inhibited CXCL10/CXCL11 release by both ASMC types. Despite these inhibitory effects, neither Ca 2+ agent affected early activation of STAT1, JNK, or p65 NF-κB. In conclusion, intracellular Ca 2+ regulated CXCL10/CXCL11 production but not early activation of the signaling molecules involved. In asthma, reduced ASM STAT1-JNK activation, increased NF-κB activation, and altered Ca 2+ handling may contribute to rapid CXCR3 ligand production and enhanced inflammatory cell recruitment.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2022
DOI: 10.1038/S41467-022-32255-7
Abstract: The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.
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.
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.
Publisher: American Thoracic Society
Date: 08-2010
Publisher: American Thoracic Society
Date: 06-2016
Publisher: Future Medicine Ltd
Date: 03-2021
Publisher: American Thoracic Society
Date: 05-2019
Publisher: Mary Ann Liebert Inc
Date: 11-2022
Abstract: Traumatic brain injury (TBI) and obesity are two common conditions in modern society both can impair neuronal integrity and neurological function. However, it is unclear whether the coexistence of both conditions will worsen outcomes. Therefore, in a rat model, we aimed to investigate whether the coexistence of TBI and a high-fat diet (HFD) has an additive effect, leading to more severe neurological impairments, and whether they are related to changes in brain protein markers of oxidative stress, inflammation, and synaptic plasticity. Sprague-Dawley rats (female, ∼250 g) were ided into HFD (43% fat) and diet (CD) (17% fat) groups for 6 weeks. Within each dietary group, half underwent a TBI by a weight-drop device, and the other half underwent sham surgery. Short-term memory and sensory function were measured at 24 h, 1 week, 3 weeks, and 6 weeks post-TBI. Brain tissues were harvested at 24 h and 6 weeks post-TBI, and markers of oxidative stress, apoptosis, inflammation, and synaptic plasticity were measured via immunostaining and Western blotting. In rats without TBI, HFD increased the pre-synaptic protein synaptophysin. In rats with TBI, HFD resulted in worsened sensory and memory function, an increase in activated macrophages, and a decrease in the endogenous antioxidant manganese superoxide dismutase (MnSOD). Our findings suggest that the additive effect of HFD and TBI worsens short term memory and sensation deficits, and may be driven by enhanced oxidative stress and inflammation.
Publisher: Elsevier BV
Date: 02-2003
DOI: 10.1067/MAI.2003.6
Abstract: Protease-activated receptors 1 and 2 (PAR-1 and PAR-2) are 7-transmembrane G protein-coupled receptors activated by serine proteases in many cell types, including monocytes-macrophages, leading to the production of pro-inflammatory mediators, cytokines, and growth factors. We determined the influence of chronic smoking and asthma on the expression of PAR-1 and PAR-2 receptors on alveolar macrophages (AMs). We used RT-PCR and immunocytochemistry with confocal microscopy to determine mRNA and protein expression of PAR-1 and PAR-2 in AMs obtained from healthy smokers, asthmatic patients, and healthy subjects. In addition, we examined the effect of IL-1beta and LPS. PAR1 mRNA was decreased, whereas PAR2 mRNA was increased in 24-hour cultured AMs from smokers when compared with values in AMs from healthy subjects. Paradoxically, there was a higher degree of PAR-1 protein staining in AMs from smokers, whereas PAR-2 staining was similar in smokers and healthy subjects. PAR-1 and PAR-2 mRNA and protein expression were similar in asthmatic patients and control subjects. IL-1beta and LPS had no effect on PAR1 and PAR2 gene expression by AMs. There is a dissociation between gene and protein expression of PAR-1 and PAR-2. PAR-1 protein overexpression in AMs from smokers might be important in the pathophysiology of chronic airways disease.
Publisher: Wiley
Date: 07-03-2018
DOI: 10.1111/JCMM.13576
Publisher: Public Library of Science (PLoS)
Date: 15-01-2014
Publisher: Impact Journals, LLC
Date: 04-05-2022
Publisher: Future Medicine Ltd
Date: 10-2021
Publisher: Public Library of Science (PLoS)
Date: 07-05-2021
DOI: 10.1371/JOURNAL.PPAT.1009575
Abstract: HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were ided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody and viral load, with RP infants having low SIV-specific antibodies and high viral loads. Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype. Interestingly, TypP had lower levels of total CD4 T cells, similar reductions in CD4/CD8 ratios and elevated activation of CD8 T cells, as measured by the levels of HLA-DR, compared to RP. Differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope ersity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.
Publisher: Wiley
Date: 27-01-2011
DOI: 10.1111/J.1440-1843.2010.01918.X
Abstract: A hallmark of asthma is airway remodelling, which includes increased deposition of extracellular matrix (ECM) protein. Viral infections may promote the development of asthma and are the most common causes of asthma exacerbations. We evaluated whether rhinovirus (RV) infection induces airway remodelling, as assessed by ECM deposition. Primary human bronchial epithelial cells and lung parenchymal fibroblasts were infected with RV-2 or RV-16, or treated with RV-16 RNA, imiquimod (Toll-like receptor (TLR) 7/8 agonist) or polyinosinic : polycytidylic acid (poly I : C) (activator of TLR 3, retinoic-acid-inducible protein I and melanoma-differentiated-associated gene 5). Changes in ECM proteins and their transcription were measured by ELISA and quantitative real-time PCR. In addition, gene expression for ECM proteins was assessed in a mouse model of RV infection. RV infection increased deposition of the ECM protein, perlecan, by human bronchial epithelial cells, and collagen V and matrix-bound vascular endothelial growth factor were increased in both human bronchial epithelial cell and fibroblast cultures. Purified RV-16 RNA, poly I : C and imiquimod induced similar increases in ECM deposition to those observed with RV-infected fibroblasts. However, only poly I : C induced ECM deposition by bronchial epithelial cells, suggesting that RV-induced ECM deposition is mediated through TLR. Furthermore, gene expression for fibronectin and collagen I was increased in lung homogenates of mice infected with RV-1b. RV infection and TLR ligands promote ECM deposition in isolated cell systems and RV induces ECM gene expression in vivo, thus demonstrating that RV has the potential to contribute to remodelling of the airways through induction of ECM deposition.
Publisher: American Society for Clinical Investigation
Date: 16-06-2016
Publisher: Japanese Society of Allergology
Date: 2006
DOI: 10.2332/ALLERGOLINT.55.215
Abstract: The airway smooth muscle is the key determinant of airway narrowing in asthma but its function in the absence of disease is unknown. Evidence for an intrinsic abnormality in the muscle in asthma is only just emerging. The airway smooth muscle is not merely a contractile cell, but also one which determines the composition of, and interacts with the extracellular matrix, and which may participate in inflammatory and allergic reactions and viral infections. The reason for the differences which have been observed in the in vitro properties of airway smooth muscle derived from asthmatic in iduals may result from an inherent "supercontractility", an increased tendency to proliferate due to the absence of an inhibitory transcription factor C/EBP-alpha, the influence of an altered extracellular matrix and/or a decrease in release of factors such as PGE(2) which would under normal circumstances inhibit both proliferation and contraction. Although long acting beta agonists and corticosteroids are successful treatments for inflammation and bronchoconstriction, the structural changes which constitute airway remodelling may require additional therapeutic intervention, the nature of which will be determined by thorough investigation of the mechanisms underlying the asthmatic phenotype.
Publisher: Frontiers Media SA
Date: 08-03-2023
DOI: 10.3389/FPSYT.2023.1026616
Abstract: Currently, the diagnosis of attention deficit hyperactivity disorder (ADHD) is solely based on behavioral tests prescribed by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). However, biomarkers can be more objective and accurate for diagnosis and evaluating treatment efficacy. Thus, this review aimed to identify potential biomarkers for ADHD. Search terms “ADHD,” and “biomarker” combined with one of “protein,” “blood/serum,” “gene,” and “neuro” were used to identify human and animal studies in PubMed, Ovid Medline, and Web of Science. Only papers in English were included. Potential biomarkers were categorized into radiographic, molecular, physiologic, or histologic markers. The radiographic analysis can identify specific activity changes in several brain regions in in iduals with ADHD. Several molecular biomarkers in peripheral blood cells and some physiologic biomarkers were found in a small number of participants. There were no published histologic biomarkers for ADHD. Overall, most associations between ADHD and potential biomarkers were properly controlled. In conclusion, a series of biomarkers in the literature are promising as objective parameters to more accurately diagnose ADHD, especially in those with comorbidities that prevent the use of DSM-5. However, more research is needed to confirm the reliability of the biomarkers in larger cohort studies.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Wiley
Date: 10-08-2015
DOI: 10.1016/J.IJDEVNEU.2015.05.009
Abstract: Maternal obesity imposes significant health risks in the offspring including diabetes and dyslipidemia. We previously showed that the hypoglycaemic agent exendin-4 (Ex-4) administered from weaning can reverse the maternal impact of 'transmitted disorders' in such offspring. However daily injection for six-weeks was required and the beneficial effect may lapse upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling period in a rodent model can reverse transmitted metabolic disorders due to maternal obesity. Maternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus. Maternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue. Short term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in preventing the development of metabolic disease.
Publisher: American Physiological Society
Date: 09-2012
Publisher: BMJ
Date: 10-06-2016
Publisher: Springer Science and Business Media LLC
Date: 07-07-2022
DOI: 10.1007/S11356-022-21454-W
Abstract: Asthma is a chronic inflammatory disease primarily characterized by inflammation and reversible bronchoconstriction. It is currently one of the leading causes of morbidity and mortality in the world. Oxidative stress further complicates the pathology of the disease. The current treatment strategies for asthma mainly involve the use of anti-inflammatory agents and bronchodilators. However, long-term usage of such medications is associated with severe adverse effects and complications. Hence, there is an urgent need to develop newer, novel, and safe treatment modalities for the management of asthma. This has therefore prompted further investigations and detailed research to identify and develop novel therapeutic interventions from potent untapped resources. This review focuses on the significance of oxidative stressors that are primarily derived from both mitochondrial and non-mitochondrial sources in initiating the clinical features of asthma. The review also discusses the biological scavenging system of the body and factors that may lead to its malfunction which could result in altered states. Furthermore, the review provides a detailed insight into the therapeutic role of nutraceuticals as an effective strategy to attenuate the deleterious effects of oxidative stress and may be used in the mitigation of the cardinal features of bronchial asthma.
Publisher: American Physiological Society
Date: 15-11-2015
DOI: 10.1152/AJPLUNG.00019.2015
Abstract: Altered ECM protein deposition is a feature in asthmatic airways. Fibronectin (Fn), an ECM protein produced by human bronchial epithelial cells (HBECs), is increased in asthmatic airways. This study investigated the regulation of Fn production in asthmatic or nonasthmatic HBECs and whether Fn modulated HBEC proliferation and inflammatory mediator secretion. The signaling pathways underlying transforming growth factor (TGF)-β1-regulated Fn production were examined using specific inhibitors for ERK, JNK, p38 MAPK, phosphatidylinositol 3 kinase, and activin-like kinase 5 (ALK5). Asthmatic HBECs deposited higher levels of Fn in the ECM than nonasthmatic cells under basal conditions, whereas cells from the two groups had similar levels of Fn mRNA and soluble Fn. TGF-β1 increased mRNA levels and ECM and soluble forms of Fn but decreased cell proliferation in both cells. The rate of increase in Fn mRNA was higher in nonasthmatic cells. However, the excessive amounts of ECM Fn deposited by asthmatic cells after TGF-β1 stimulation persisted compared with nonasthmatic cells. Inhibition of ALK5 completely prevented TGF-β1-induced Fn deposition. Importantly, ECM Fn increased HBEC proliferation and IL-6 release, decreased PGE 2 secretion, but had no effect on VEGF release. Soluble Fn had no effect on cell proliferation and inflammatory mediator release. Asthmatic HBECs are intrinsically primed to produce more ECM Fn, which when deposited into the ECM, is capable of driving remodeling and inflammation. The increased airway Fn may be one of the key driving factors in the persistence of asthma and represents a novel, therapeutic target.
Publisher: Wiley
Date: 18-10-2015
DOI: 10.1111/RESP.12657
Publisher: Portland Press Ltd.
Date: 31-07-2018
DOI: 10.1042/CS20180398
Abstract: Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD), which is correlated with disease severity and negatively affects lung function in these patients. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) activated by various stress stimuli, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) and is known to regulate cell proliferation. ASM cells from COPD patients are hyperproliferative to mitogens in vitro. However, the role of ASK1 in ASM growth is not established. Here, we aim to determine the effects of ASK1 inhibition on ASM growth and pro-mitogenic signaling using ASM cells from COPD patients. We found greater expression of ASK1 in ASM bundles of COPD lung when compared with non-COPD. Pre-treatment of ASM cells with highly selective ASK1 inhibitor, TC ASK 10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF, and EGF 72 h)-induced ASM growth as measured by CyQUANT assay. Further, molecular targetting of ASK1 using siRNA in ASM cells prevented mitogen-induced cell growth. In addition, to anti-mitogenic potential, ASK1 inhibitor also prevented TGFβ1-induced migration of ASM cells in vitro. Immunoblotting revealed that anti-mitogenic effects are mediated by C-Jun N-terminal kinase (JNK) and p38MAP kinase-signaling pathways as evident by reduced phosphorylation of downstream effectors JNK1/2 and p38MAP kinases, respectively, with no effect on extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2). Collectively, these findings establish the anti-mitogenic effect of ASK1 inhibition and identify a novel pathway that can be targetted to reduce or prevent excessive ASM mass in COPD.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2018
Publisher: European Respiratory Society
Date: 15-09-2018
Publisher: Elsevier BV
Date: 10-2014
Publisher: MDPI AG
Date: 06-05-2021
Abstract: Air pollution is the 9th cause of the overall disease burden globally. The solid component in the polluted air, particulate matters (PMs) with a diameter of 2.5 μm or smaller (PM2.5) possess a significant health risk to several organ systems. PM2.5 has also been shown to cross the blood–placental barrier and circulate in foetal blood. Therefore, it is considered an intrauterine environmental toxin. Exposure to PM2.5 during the perinatal period, when the foetus is particularly susceptible to developmental defects, has been shown to reduce birth weight and cause preterm birth, with an increase in adult disease susceptibility in the offspring. However, few studies have thoroughly studied the health outcome of foetuses due to intrauterine exposure and the underlying mechanisms. This perspective summarises currently available evidence, which suggests that intrauterine exposure to PM2.5 promotes oxidative stress and inflammation in a similar manner as occurs in response to direct PM exposure. Oxidative stress and inflammation are likely to be the common mechanisms underlying the dysfunction of multiple systems, offering potential targets for preventative strategies in pregnant mothers for an optimal foetal outcome.
Publisher: Wiley
Date: 18-08-2015
DOI: 10.1111/JCMM.12593
Publisher: American Physiological Society
Date: 06-2020
DOI: 10.1152/AJPLUNG.00051.2020
Abstract: Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patients with chronic obstructive pulmonary disease (COPD). It is capable of differentiating emphysema-related air trapping with nonemphysematous air trapping (small airway disease), which helps to identify the extent and localization of the disease. Most studies evaluating the gene expression in smokers and COPD patients related this to spirometric measurements, but none have investigated the relationship with CT-based measurements of lung structure. The current study aimed to examine gene expression profiles of brushed bronchial epithelial cells in association with the PRM-defined CT-based measurements of emphysema (PRM Emph ) and small airway disease (PRM fSAD ). Using the Top Institute Pharma (TIP) study cohort (COPD = 12 and asymptomatic smokers = 32), we identified a gene expression signature of bronchial brushings, which was associated with PRM Emph in the lungs. One hundred thirty-three genes were identified to be associated with PRM Emph . Among the most significantly associated genes, CXCL11 is a potent chemokine involved with CD8 + T cell activation during inflammation in COPD, indicating that it may play an essential role in the development of emphysema. The PRM Emph signature was then replicated in two independent data sets. Pathway analysis showed that the PRM Emph signature is associated with proinflammatory and notch signaling pathways. Together these findings indicate that airway epithelium may play a role in the development of emphysema and/or may act as a biomarker for the presence of emphysema. In contrast, its role in relation to functional small airways disease is less clear.
Publisher: Hindawi Limited
Date: 08-05-2020
DOI: 10.1155/2020/4260204
Abstract: Particulate matter with an aerodynamic diameter equal or less than 2.5 micrometers (PM2.5) is associated with the development of chronic obstructive pulmonary disease (COPD). The mechanisms by which PM2.5 accelerates disease progression in COPD are poorly understood. In this study, we aimed to investigate the effect of PM2.5 on lung injury in rats with hallmark features of COPD. Cardinal features of human COPD were induced in a rat model by repeated cigarette smoke inhalation and bacterial infection for 8 weeks. Then, from week 9 to week 16, some of these rats with COPD were subjected to real-time concentrated atmospheric PM2.5. Lung function, pathology, inflammatory cytokines, oxidative stress, and mucus and collagen production were measured. As expected, the COPD rats had developed emphysema, inflammation, and deterioration in lung function. PM2.5 exposure resulted in greater lung function decline and histopathological changes, as reflected by increased Mucin (MUC) 5ac, MUC5b, Collagen I, Collagen III, and the profibrotic cytokine α -smooth muscle-actin (SMA), transforming growth factor- (TGF-) β 1 in lung tissues. PM2.5 also aggravated inflammation, increasing neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF) and cytokines including Interleukin- (IL-) 1 β , granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-4. The likely mechanism is through oxidative stress as antioxidants levels were decreased, whereas oxidants were increased, indicating a detrimental shift in the oxidant-antioxidant balance. Altogether, these results suggest that PM2.5 exposure could promote the development of COPD by impairing lung function and exacerbating pulmonary injury, and the potential mechanisms are related to inflammatory response and oxidative stress.
Publisher: Wiley
Date: 30-05-2020
DOI: 10.14814/PHY2.14459
Publisher: AMPCo
Date: 21-07-2021
DOI: 10.5694/MJA2.51183
Publisher: Springer Singapore
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 11-04-2017
DOI: 10.1038/SREP46166
Abstract: Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.
Publisher: BMJ
Date: 20-06-2017
Publisher: Wiley
Date: 17-06-2020
DOI: 10.1111/NYAS.14411
Publisher: MDPI AG
Date: 29-11-2021
Abstract: Chronic airway inflammation and oxidative stress play crucial roles in the pathogenesis of chronic inflammatory lung diseases, with airway inflammation being a key driving mechanism of oxidative stress in the lungs. Inflammatory responses in the lungs activate neutrophils and/or eosinophils, leading to the generation of hypohalous acids (HOX). These HOX oxidants can damage the extracellular matrix (ECM) structure and may influence cell–ECM interactions. The ECM of the lung provides structural, mechanical, and biochemical support for cells and determines the airway structure. One of the critical cells in chronic respiratory disease is the fibroblast. Thus, we hypothesised that primary human lung fibroblasts (PHLF) exposed to an oxidised cell-derived ECM will result in functional changes to the PHLF. Here, we show that PHLF adhesion, proliferation, and inflammatory cytokine secretion is affected by exposure to HOX-induced oxidisation of the cell-derived ECM. Furthermore, we investigated the impact on fibroblast function from the presence of haloamines in the ECM. Haloamines are chemical by-products of HOX and, like the HOX, haloamines can also modify the ECM. In conclusion, this study revealed that oxidising the cell-derived ECM might contribute to functional changes in PHLF, a key mechanism behind the pathogenesis of inflammatory lung diseases.
Publisher: American Thoracic Society
Date: 05-2023
Publisher: Wiley
Date: 19-08-2015
DOI: 10.1111/RESP.12606
Abstract: Exacerbations of allergic asthma are often triggered by respiratory viral infections. We have previously shown that in a T-helper type 2 (Th2)-biased cytokine environment, mouse and human airway epithelial cells (AEC) exhibit increased expression of pro-inflammatory and anti-viral genes in response to synthetic double-stranded ribonucleic acid (dsRNA), a virus-like stimulus. This implies coordinated regulation of gene expression, suggesting possible involvement of microRNA. To investigate this, we developed a novel approach to identifying candidate microRNA using online databases, then confirmed their expression by quantitative real-time polymerase chain reaction (qRT-PCR). Using a list of genes of interest, defined on the basis of the previous study as being up-regulated in a Th2 environment, we searched mouse and human microRNA databases for possible regulatory microRNA, and selected 10 candidates that were conserved across species or predicted by more than one human database. Expression of these microRNA was tested by qRT-PCR, in primary human AEC pre-treated with Th2 cytokines and exposed to dsRNA. Expression of hsa-miR-139-5p, miR-423-5p and miR-542-3p was significantly decreased in Th2 pre-treated AEC, and miR-135a-5p exhibited a trend towards decreased expression. Further database searches confirmed that these microRNA regulated additional pro-inflammatory and anti-viral response genes for which expression had previously been shown to be up-regulated, confirming the validity of this approach. Our study demonstrates the value of using multiple online databases to identify candidate regulatory microRNA and provides the first evidence that in an allergic environment, microRNA may be important in altering the pro-inflammatory and anti-viral responses of human AEC during exacerbations of asthma.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.PUPT.2010.12.002
Abstract: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterised by chronic bronchitis, largely irreversible remodelling of the small airways, and emphysematous destruction of the alveoli. COPD is projected to be the third leading cause of death worldwide by 2020. COPD often results from prolonged exposure to irritants such as cigarette smoke or inhaled particulates. Current pharmacotherapies for COPD are unable to reverse the pathological changes of this disease, and this is partially due to a limited understanding of the intricate mechanisms by which chronic exposure lead to the different pathological components of COPD. This review examines how the mechanisms that underlie various components of COPD can be modelled in vitro, specifically using cigarette smoke extract with cells cultured from primary human lung tissue, and how the effectiveness of current and novel pharmacotherapies on successfully attenuating these pathological changes can also be examined in vitro.
Publisher: BMJ
Date: 03-03-2012
DOI: 10.1136/THORAXJNL-2011-200160
Abstract: 20-30% of patients with asthma have neutrophilic airway inflammation and reduced responsiveness to steroid therapy. They often have chronic airway bacterial colonisation and Haemophilus influenzae is one of the most commonly isolated bacteria. The relationship between chronic airway colonisation and the development of steroid-resistant neutrophilic asthma is unclear. To investigate the relationship between H influenzae respiratory infection and neutrophilic asthma using mouse models of infection and ovalbumin (OVA)-induced allergic airways disease. BALB/c mice were intratracheally infected with H influenzae (day 10), intraperitoneally sensitised (day 0) and intranasally challenged (day 12-15) with OVA. Treatment groups were administered dexamethasone intranasally during OVA challenge. Infection, allergic airways disease, steroid sensitivity and immune responses were assessed (days 11, 16 and 21). The combination of H influenzae infection and allergic airways disease resulted in chronic lung infection that was detected on days 11, 16 and 21 (21, 26 and 31 days after infection). Neutrophilic allergic airways disease and T helper 17 cell development were induced, which did not require active infection. Importantly, all features of neutrophilic allergic airways disease were steroid resistant. Toll-like receptor 4 expression and activation of phagocytes was reduced, but most significantly the influx and/or development of phagocytosing neutrophils and macrophages into the airways was inhibited. The combination of infection and allergic airways disease promotes bacterial persistence, leading to the development of a phenotype similar to steroid-resistant neutrophilic asthma and which may result from dysfunction in innate immune cells. This indicates that targeting bacterial infection in steroid-resistant asthma may have therapeutic benefit.
Publisher: Elsevier BV
Date: 10-2009
Abstract: The treatment of asthma relies on the use of the following two major drug classes: beta(2)-agonists, both short acting and long acting and corticosteroids (CSs). Although the properties of each drug class are well described, their use in combination delivered either separately or through one device has provided some clear and important clinical advantages. The mechanisms underlying these interactions have emerged as novel and provocative. beta(2)-Agonists can stimulate the glucocorticoid receptor (GR) and promote its translocation to the nucleus, resulting in increased CS-mediated gene transcription. In structural airway cells, such as fibroblasts and smooth muscle, this gene transcription is associated with the formation of a complex between the GR and another transcription factor, CCAAT enhancer-binding protein (C/EBP)-alpha. Airway smooth muscle cells from persons with asthma are deficient in C/EBP-alpha, which may explain the finding that CSs do not inhibit the proliferation of these cells in vitro. Whether this deficiency can explain the increased bulk of muscle in the asthmatic airway remains to be established. beta(2)-Agonists can inhibit mast cell mediator release, but this response is susceptible to desensitization, a process that CSs can inhibit. CSs also can increase the transcription of the beta(2)-receptor gene in the lung and the nasal mucosa. These effects of CSs mitigate against the reduced transcription of beta(2)-receptors, which occurs as a consequence of long-term beta(2)-agonist administration. Delineation of the exact mechanisms underlying these effects will ensure rational, direct therapy.
Publisher: Public Library of Science (PLoS)
Date: 07-06-2013
Publisher: American Physiological Society
Date: 2007
DOI: 10.1152/AJPLUNG.00230.2006
Abstract: Increased levels of IL-6 are documented in asthma, but its contribution to the pathology is unknown. Asthma is characterized by airway wall thickening due to increased extracellular matrix deposition, inflammation, angiogenesis, and airway smooth muscle (ASM) mass. IL-6 binds to a specific membrane-bound receptor, IL-6 receptor-α (mIL-6Rα), and subsequently to the signaling protein gp130. Alternatively, IL-6 can bind to soluble IL-6 recpetor-α (sIL-6Rα) to stimulate membrane receptor-deficient cells, a process called trans-signaling. We discovered that primary human ASM cells do not express mIL-6Rα and, therefore, investigated the effect of IL-6 trans-signaling on the pro-remodeling phenotype of ASM. ASM required sIL-6Rα to activate signal transducer and activator 3, with no differences observed between cells from asthmatic subjects compared with controls. Further analysis revealed that IL-6 alone or with sIL-6Rα did not induce release of matrix-stimulating factors (including connective tissue growth factor, fibronectin, or integrins) and had no effect on mast cell adhesion to ASM or ASM proliferation. However, in the presence of sIL-6Rα, IL-6 increased eotaxin and VEGF release and may thereby contribute to local inflammation and vessel expansion in airway walls of asthmatic subjects. As levels of sIL-6Rα are increased in asthma, this demonstration of IL-6 trans-signaling in ASM has relevance to the development of airway remodeling.
Publisher: Elsevier
Date: 2019
Publisher: Elsevier BV
Date: 11-2021
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000447329
Abstract: b i Background: /i /b Transbronchial lung biopsy using a cryoprobe is a novel way of s ling lung parenchyma. Correlation of freezing time with biopsy size and complications has not been evaluated in vivo. b i Objectives: /i /b The primary aim of the study is to evaluate the correlation between transbronchial cryobiopsy freezing time and size. The secondary aims are to evaluate histological quality of the biopsy and evaluate procedure-associated complications. b i Methods: /i /b Transbronchial lung cryobiopsies were obtained from two anaesthetised sheep using a 1.9-mm cryoprobe inserted into a flexible bronchoscope under fluoroscopic guidance. Freezing times ranged from 1 to 6 s (n = 49). The cryobiopsies were evaluated histologically with respect to their size and quality. Complications of bleeding and pneumothorax were recorded. b i Results: /i /b The mean cross-sectional area of the cryobiopsy ranged from 4.7 ± 2.1 to 15.7 ± 15.3 mm sup /sup . There was a significant positive correlation between increasing freezing time and cryobiopsy cross-sectional area (p = 0.028). All biopsies contained lung tissue with preserved parenchyma. Crush and freeze artefacts were not observed and tissue architecture was intact in all specimens. Small blood vessels and terminal bronchioles were observed in 88% of specimens. All cryobiopsies caused nil or mild haemorrhage with the exception of only 1 episode of severe haemorrhage at 6 s freezing time. Pneumothoraces occurred at 2, 5 and 6 s freezing time and required chest tube insertion. The most significant haemorrhage and pneumothoraces occurred at 5 and 6 s. Our results suggest an initial freezing time of 3 s can provide the maximal biopsy size while minimising major complications. b i Conclusion: /i /b The optimal transbronchial cryobiopsy freezing time is initially 3 s. This time is associated with minimal complications and large artefact-free biopsies.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JACI.2018.04.037
Abstract: Both obesity and high dietary fat intake activate the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. We aimed to examine NLRP3 inflammasome activity in the airways of obese asthmatic patients after macronutrient overload and in immune cells challenged by inflammasome triggers. Study 1 was a cross-sectional observational study of nonobese (n = 51) and obese (n = 76) asthmatic adults. Study 2 was a randomized, crossover, acute feeding study in 23 asthmatic adults (n = 12 nonobese and n = 11 obese subjects). Subjects consumed 3 isocaloric meals on 3 separate occasions (ie, saturated fatty acid, n-6 polyunsaturated fatty acid, and carbohydrate) and were assessed at 0 and 4 hours. For Studies 1 and 2, airway inflammation was measured based on sputum differential cell counts, IL-1β protein levels (ELISA), and sputum cell gene expression (Nanostring nCounter). In Study 3 peripheral blood neutrophils and monocytes were isolated by using Ficoll density gradient and magnetic bead separation and incubated with or without palmitic acid, LPS, or TNF-α for 24 hours, and IL-1β release was measured (ELISA). In Study 1 NLRP3 and nucleotide oligomerization domain 1 (NOD1) gene expression was upregulated, and sputum IL-1β protein levels were greater in obese versus nonobese asthmatic patients. In Study 2 the saturated fatty acid meal led to increases in sputum neutrophil percentages and sputum cell gene expression of Toll-like receptor 4 (TLR4) and NLRP3 at 4 hours in nonobese asthmatic patients. In Study 3 neutrophils and monocytes released IL-1β when challenged with a combination of palmitic acid and LPS or TNF-α. The NLRP3 inflammasome is a potential therapeutic target in asthmatic patients. Behavioral interventions that reduce fatty acid exposure, such as weight loss and dietary saturated fat restriction, warrant further exploration.
Publisher: S. Karger AG
Date: 2021
DOI: 10.1159/000515328
Abstract: b i Background: /i /b Emerging evidence has indicated that small airway dysfunction (SAD) contributes to the clinical expression of asthma. b i Objectives: /i /b The aim of the study was to explore the relationships of SAD assessed by forced expiratory flow between 25 and 75% (FEF sub –75 /sub %), with clinical and inflammatory profile and treatment responsiveness in asthma. b i Method: /i /b In study I, dyspnea intensity (Borg scale), chest tightness, wheezing and cough (visual analog scales, VASs), and pre- and post-methacholine challenge testing (MCT) were analyzed in asthma patients with SAD and non-SAD. In study II, asthma subjects with SAD and non-SAD underwent sputum induction, and inflammatory mediators in sputum were detected. Asthma patients with SAD and non-SAD receiving fixed treatments were prospectively followed up for 4 weeks in study III. Spirometry, Asthma Control Questionnaire (ACQ), and Asthma Control Test (ACT) were carried out to define treatment responsiveness. b i Results: /i /b SAD subjects had more elevated ΔVAS for dyspnea ( i /i = 0.027) and chest tightness ( i /i = 0.032) after MCT. Asthma patients with SAD had significantly elevated interferon (IFN)-γ in sputum ( i /i & #x3c 0.05), and Spearman partial correlation found FEF sub –75 /sub % significantly related to IFN-γ and interleukin-8 (both having i /i & #x3c 0.05). Furthermore, multivariable regression analysis indicated SAD was significantly associated with worse treatment responses (decrease in ACQ ≥0.5 and increase in ACT ≥3) ( i /i = 0.022 and i /i = 0.032). b i Conclusions: /i /b This study indicates that SAD in asthma predisposes patients to greater dyspnea intensity and chest tightness during bronchoconstriction. SAD patients with asthma are characterized by non-type 2 inflammation that may account for poor responsiveness to therapy.
Publisher: S. Karger AG
Date: 2021
DOI: 10.1159/000510793
Abstract: b i Background: /i /b Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking. b i Objective: /i /b To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population. b i Methods: /i /b We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma ( i n /i = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations. b i Results: /i /b Of 546 participants, 61.9% had no exacerbations ( i n /i = 338), 29.6% had few exacerbations ( i n /i = 162), and 8.4% were exacerbation prone ( i n /i = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all i /i & #x3c 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV sub /sub (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers. b i Conclusion: /i /b EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2023
DOI: 10.1186/S13578-023-00998-5
Abstract: Sex differences in susceptibility, severity, and progression are prevalent for various diseases in multiple organ systems. This phenomenon is particularly apparent in respiratory diseases. Asthma demonstrates an age-dependent pattern of sexual dimorphism. However, marked differences between males and females exist in other pervasive conditions such as chronic obstructive pulmonary disease (COPD) and lung cancer. The sex hormones estrogen and testosterone are commonly considered the primary factors causing sexual dimorphism in disease. However, how they contribute to differences in disease onset between males and females remains undefined. The sex chromosomes are an under-investigated fundamental form of sexual dimorphism. Recent studies highlight key X and Y-chromosome-linked genes that regulate vital cell processes and can contribute to disease-relevant mechanisms. This review summarises patterns of sex differences in asthma, COPD and lung cancer, highlighting physiological mechanisms causing the observed dimorphism. We also describe the role of the sex hormones and present candidate genes on the sex chromosomes as potential factors contributing to sexual dimorphism in disease.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.ENVRES.2022.113378
Abstract: Airborne particulate matter (PM) comprises both solid and liquid particles, including carbon, sulphates, nitrate, and toxic heavy metals, which can induce oxidative stress and inflammation after inhalation. These changes occur both in the lung and systemically, due to the ability of the small-sized PM (i.e. diameters ≤2.5 μm, PM
Publisher: MDPI AG
Date: 06-12-2022
DOI: 10.3390/JCM11237241
Abstract: Background: Skeletal muscle mass (SMM) has been suggested to be associated with multiple health-related outcomes. However, the potential influence of SMM on asthma has not been largely explored. Objective: To study the association between SMM and clinical features of asthma, including asthma control and exacerbation, and to construct a model based on SMM to predict the risk of asthma exacerbation (AEx). Methods: In this prospective cohort study, we consecutively recruited patients with asthma (n = 334), classified as the SMM Normal group (n = 223), SMM Low group (n = 88), and SMM High group (n = 23). We investigated the association between SMM and clinical asthma characteristics and explored the association between SMM and asthma control and AEx within a 12-month follow-up period. Based on SMM, an exacerbation prediction model was developed, and the overall performance was externally validated in an independent cohort (n = 157). Results: Compared with the SMM Normal group, SMM Low group exhibited more airway obstruction and worse asthma control, while SMM High group had a reduced eosinophil percentage in induced sputum. Furthermore, SMM Low group was at a significantly increased risk of moderate-to-severe exacerbation compared with the SMM Normal group (relative risk adjusted 2.02 [95% confidence interval (CI), 1.35–2.68] p = 0.002). In addition, a model involving SMM was developed which predicted AEx (area under the curve: 0.750, 95% CI: 0.691–0.810). Conclusions: Low SMM was an independent risk factor for future AEx. Furthermore, a model involving SMM for predicting the risk of AEx in patients with asthma indicated that assessment of SMM has potential clinical implications for asthma management.
Publisher: Public Library of Science (PLoS)
Date: 06-03-2013
Publisher: American Thoracic Society
Date: 10-2000
DOI: 10.1164/AJRCCM.162.4.9910097
Abstract: An imbalance between proteases and antiproteases may play a role in emphysema, which is characterized by increased degradation of extracellular matrix, and in airway remodeling in chronic bronchitis and asthma, in which there is increased collagen deposition. We assessed the effect of smoking on release of matrix metalloprotease-9 (MMP-9) and of its inhibitor, tissue inhibitor of metalloprotease-1 (TIMP-1), from alveolar macrophages, and determined the effects of proinflammatory (interleukin [IL]-1beta and lipopolysaccharide [LPS]) and antiinflammatory (IL-10) stimuli on the release of MMP-9 and TIMP-1. We performed bronchoalveolar lavage in 11 smokers and 11 nonsmokers, and cultured airway macrophages in the presence of control medium, IL-1beta, and LPS. Airway macrophages from smokers released greater amounts of MMP-9 and TIMP-1 at baseline and in response to IL-1beta and LPS than did those of nonsmokers. Airway macrophages from smokers produced more TNF-alpha and IL-10. IL-10 increased TIMP-1 release without modifying that of MMP-9, leading to a decrease in the MMP-9 to TIMP-1 ratio. Anti-IL-10 antibody had no effect on MMP-9 production induced by LPS. We conclude that the release of proteases and antiproteases by airway macrophages is increased in cigarette smokers, and can be regulated by exogenous IL-10.
Publisher: Frontiers Media SA
Date: 24-11-2022
DOI: 10.3389/FPSYT.2022.1053937
Abstract: This systematic review aimed to evaluate the efficacy of exercise programmes with nicotine replacement therapy (NRT) for smoking cessation in adults. Nicotine addiction is mediated by dopamine. Exercise can also activate the dopamine reward system. Therefore, exercise may effectively facilitate NRT to reduce cigarette cravings and withdrawal symptoms. Clinical trials between 2000 and 2022 used exercise protocols of any intensity for smoking cessation, in current smokers or recent quitters of both genders, aged 18–70, without severe diseases and pregnancy. Mental disorders were not excluded, as exercise can improve mental health status. Therefore, it may be as effective among people with mental health issues as the general population in preventing nicotine cravings and supporting abstinence. Four databases (PubMed, Embase, Cochrane, and Medline) were searched for papers in English using the terms “nicotine replacement therapy’, “exercise,” and “smoking cessation.” Titles and abstracts were screened for potentially eligibility before full texts were reviewed. S le size, gender, study duration, and age was then extracted. The certainty of the evidence was assessed using Joanna Briggs Institute’s (JBI’s) GRADE approach. Seventeen studies were identified with a total of 3,191 participants. Three studies are not a randomised control study. There was moderate-high quality evidence that exercise can aid NRT in promoting smoking cessation in the short term. Several studies reported temporary reductions in cravings however, only one trial reported a decrease in cigarette consumption due to exercise intervention and one demonstrated increased smoking abstinence at 1 year of the intervention. Exercise with NRT aids smoking cessation in the short term, but no evidence suggests its efficacy in the long term when combined. Future trials should include larger s le sizes and strategies to increase exercise adherence.
Publisher: Frontiers Media SA
Date: 05-02-2020
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.CBI.2021.109706
Abstract: The challenges and difficulties associated with conventional drug delivery systems have led to the emergence of novel, advanced targeted drug delivery systems. Therapeutic drug delivery of proteins and peptides to the lungs is complicated owing to the large size and polar characteristics of the latter. Nevertheless, the pulmonary route has attracted great interest today among formulation scientists, as it has evolved into one of the important targeted drug delivery platforms for the delivery of peptides, and related compounds effectively to the lungs, primarily for the management and treatment of chronic lung diseases. In this review, we have discussed and summarized the current scenario and recent developments in targeted delivery of proteins and peptide-based drugs to the lungs. Moreover, we have also highlighted the advantages of pulmonary drug delivery over conventional drug delivery approaches for peptide-based drugs, in terms of efficacy, retention time and other important pharmacokinetic parameters. The review also highlights the future perspectives and the impact of targeted drug delivery on peptide-based drugs in the coming decade.
Publisher: Frontiers Media SA
Date: 28-02-2018
Publisher: Elsevier BV
Date: 09-2021
Publisher: Georg Thieme Verlag KG
Date: 13-11-2012
Publisher: Elsevier BV
Date: 02-2021
Publisher: American Physiological Society
Date: 06-2011
DOI: 10.1152/AJPLUNG.00411.2010
Abstract: Airway remodeling, which includes increases in the extracellular matrix (ECM), is a characteristic feature of asthma and is correlated to disease severity. Rhinovirus (RV) infections are associated with increased risk of asthma development in young children and are the most common cause of asthma exacerbations. We examined whether viral infections can increase ECM deposition and whether this increased ECM modulates cell proliferation and migration. RV infection of nonasthmatic airway smooth muscle (ASM) cells significantly increased the deposition of fibronectin (40% increase, n = 12) and perlecan (80% increase, n = 14), while infection of asthmatic ASM cells significantly increased fibronectin (75% increase, n = 9) and collagen IV (15% increase, n = 9). We then treated the ASM cells with the Toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid, imiquimod, and pure RV RNA and were able to show that the mechanism through which RV induced ECM deposition was via the activation of TLR3 and TLR7/8. Finally, we assessed whether the virus-induced ECM was bioactive by measuring the amount of migration and proliferation of virus-naive cells that seeded onto the ECM. Basically, ECM from asthmatic ASM cells induced twofold greater migration of virus-naive ASM cells than ECM from nonasthmatic ASM cells, and these rates of migration were further increased on RV-modulated ECM. Increased migration on the RV-modulated ECM was not due to increased cell proliferation, as RV-modulated ECM decreased the proliferation of virus-naive cells. Our results suggest that viruses may contribute to airway remodeling through increased ECM deposition, which in turn may contribute to increased ASM mass via increased cell migration.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Future Medicine Ltd
Date: 05-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2020
Publisher: European Respiratory Society
Date: 09-09-2023
Publisher: Springer Science and Business Media LLC
Date: 17-04-2018
Publisher: Springer Nature Singapore
Date: 2022
Publisher: Frontiers Media SA
Date: 13-02-2017
Publisher: MDPI AG
Date: 15-10-2020
DOI: 10.3390/IJMS21207640
Abstract: Current therapeutic options for obesity often require pharmacological intervention with dietary restrictions. Obesity is associated with underlying inflammation due to increased tissue macrophage infiltration, and recent evidence shows that inflammation can drive obesity, creating a feed forward mechanism. Therefore, targeting obesity-induced macrophage infiltration may be an effective way of treating obesity. Here, we developed cargo-less liposomes (UTS-001) using 1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC (synthetic phosphatidylcholine) as a single-agent to manage weight gain and related glucose disorders due to high fat diet (HFD) consumption in mice. UTS-001 displayed potent immunomodulatory properties, including reducing resident macrophage number in both fat and liver, downregulating liver markers involved in gluconeogenesis, and increasing marker involved in thermogenesis. As a result, UTS-001 significantly enhanced systemic glucose tolerance in vivo and insulin-stimulated cellular glucose uptake in vitro, as well as reducing fat accumulation upon ad libitum HFD consumption in mice. UTS-001 targets tissue residence macrophages to suppress tissue inflammation during HFD-induced obesity, resulting in improved weight control and glucose metabolism. Thus, UTS-001 represents a promising therapeutic strategy for body weight management and glycaemic control.
Publisher: European Respiratory Society (ERS)
Date: 04-2021
DOI: 10.1183/23120541.00802-2020
Abstract: Reduction of COL4A3, one of the six isoforms of collagen 4, in asthmatic airways results in increased inflammation and angiogenesis, implicating it as a central part of asthma pathogenesis. However, to date, the path underlying these diminished COL4A3 levels has been elusive. This study investigated a possible mechanism underlying the reduction of COL4A3 expression. Bronchial biopsies of 76 patients with asthma and 83 controls were subjected to RNA-sequencing and DNA methylation bead arrays to identify expression and methylation changes. The binding of ZNF263 was analysed by chromatin-immunoprecipitation sequencing coupled with quantitative (q)PCR. Effects of ZNF263 silencing, using small interfering RNA, on the COL4A3 expression were studied using qPCR. COL4A3 expression was significantly reduced in bronchial biopsies compared to healthy controls, whereas DNA methylation levels at cg11797365 were increased. COL4A3 expression levels were significantly low in asthmatics without inhaled corticosteroid (ICS) use, whereas the expression was not statistically different between asthmatics using ICS and controls. Methylation levels at cg11797365 in vitro were increased upon consecutive rhinovirus infections. Our data indicate an epigenetic modification as a contributing factor for the loss of COL4A3 expression in asthmatic airway epithelium.
Publisher: European Respiratory Society (ERS)
Date: 25-06-2018
DOI: 10.1183/13993003.00310-2018
Abstract: Chronic mucus hypersecretion (CMH) contributes to the morbidity and mortality of asthma, and remains uncontrolled by current therapies in the subset of patients with severe, steroid-resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as interleukin (IL)-1β, provides a potential mechanism that influences CMH. This study investigated mechanisms underlying CMH by comparing IL-1β-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production
Publisher: Elsevier BV
Date: 04-2017
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 03-2023
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.
Publisher: Stichting Nase
Date: 2017
DOI: 10.4193/RHIN16.215
Publisher: Public Library of Science (PLoS)
Date: 28-11-2018
Publisher: Bentham Science Publishers Ltd.
Date: 11-2022
DOI: 10.2174/1381612828666220413103831
Abstract: Several factors exist that limit the efficacy of lung cancer treatment. These may be tumor-specific delivery of therapeutics, airway geometry, humidity, clearance mechanisms, presence of lung diseases, and therapy against tumor cell resistance. Advancements in drug delivery using nanotechnology based multifunctional nanocarriers, have emerged as a viable method for treating lung cancer with more efficacy and fewer adverse effects. This review does a thorough and critical examination of effective nano-enabled approaches for lung cancer treatment, such as nano-assisted drug delivery systems. In addition, to therapeutic effectiveness, researchers have been working to determine several strategies to produce nanotherapeutics by adjusting the size, drug loading, transport, and retention. Personalized lung tumor therapies using sophisticated nano modalities have the potential to provide great therapeutic advantages based on in idual unique genetic markers and disease profiles. Overall, this review provides comprehensive information on newer nanotechnological prospects for improving the management of apoptosis in lung cancer.
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 19-02-2019
Publisher: Wiley
Date: 29-10-2022
Abstract: COVID‐19 remains a life‐threatening infectious disease worldwide. Several bio‐active agents have been tested and evaluated in an effort to contain this disease. Unfortunately, none of the therapies have been successful, owing to their safety concerns and the presence of various adverse effects. Various countries have developed vaccines as a preventive measure however, they have not been widely accepted as effective strategies. The virus has proven to be exceedingly contagious and lethal, so finding an effective treatment strategy has been a top priority in medical research. The significance of vitamin D in influencing many components of the innate and adaptive immune systems is examined in this study. This review aims to summarize the research on the use of vitamin D for COVID‐19 treatment and prevention. Vitamin D supplementation has now become an efficient option to boost the immune response for all ages in preventing the spread of infection. Vitamin D is an immunomodulator that treats infected lung tissue by improving innate and adaptive immune responses and downregulating the inflammatory cascades. The preventive action exerted by vitamin D supplementation (at a specific dose) has been accepted by several observational research investigations and clinical trials on the avoidance of viral and acute respiratory dysfunctions. To assess the existing consensus about vitamin D supplementation as a strategy to treat and prevent the development and progression of COVID‐19 disease, this review intends to synthesize the evidence around vitamin D in relation to COVID‐19 infection.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.CHOM.2022.08.005
Abstract: Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis s les and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group.
Publisher: American Physiological Society
Date: 09-2020
DOI: 10.1152/AJPLUNG.00244.2020
Abstract: Epidemiological studies suggest that environmental factors (e.g., air pollution) can influence the spread and infectivity of coronavirus disease 2019 (COVID-19) however, very few papers have investigated or discussed the mechanism behind the phenomenon. Given the fact that pollution will increase as social distancing rules are relaxed, we summarized the current understanding of how air pollution may affect COVID-19 transmission and discussed several possible mechanisms. Air pollution exposure can dysregulate the human immune response and make people more susceptible to infections, and affect infectivity. For ex le, in response to exposure to air pollution, angiotensin-converting enzyme 2 will increase, which is the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This may increase the efficiency of viral infection. It is also possible that air pollution can facilitate SARS-CoV-2 spread by increasing the transmission, and potentially, SARS-CoV-2 can also survive longer when attached to a pollutant.
Publisher: MDPI AG
Date: 21-07-2023
DOI: 10.3390/JCM12144815
Abstract: Chronic obstructive pulmonary disease (COPD) is a complex and serious disease that is characterized by dyspnea, fatigue, decreased exercise tolerance, peripheral muscle dysfunction, and mood disorders. These manifestations are successfully treated with pulmonary rehabilitation, a comprehensive intervention and holistic approach designed to improve the physical and psychological condition of people with COPD. Exercise is a big component of pulmonary rehabilitation programs, but the efficacy of non-traditional forms of exercise as used in alternative medicine is poorly understood. Here, we aim to address this gap in knowledge and summarize the clinical evidence for the use of traditional exercise regimens in the pulmonary rehabilitation of COPD patients.
Publisher: Wiley
Date: 21-03-2022
DOI: 10.1111/IMCB.12537
Abstract: Increased inflammasome responses are strongly implicated in inflammatory diseases however, their specific roles are incompletely understood. Therefore, we sought to examine the roles of nucleotide‐binding oligomerization domain–like receptor (NLR) family, pyrin domain–containing 3 (NLRP3) and absent in melanoma‐2 (AIM2) inflammasomes in cigarette smoke–induced inflammation in a model of experimental chronic obstructive pulmonary disease (COPD). We targeted NLRP3 with the inhibitor MCC950 given prophylactically or therapeutically and examined Aim2 −/− mice in cigarette smoke–induced experimental COPD. MCC950 treatment had minimal effects on disease development and/or progression. Aim2 −/− mice had increased airway neutrophils with decreased caspase‐1 levels, independent of changes in lung neutrophil chemokines. Suppressing neutrophils with anti‐Ly6G in experimental COPD in wild‐type mice reduced neutrophils in bone marrow, blood and lung. By contrast, anti‐Ly6G treatment in Aim2 −/− mice with experimental COPD had no effect on neutrophils in bone marrow, partially reduced neutrophils in the blood and had no effect on neutrophils or neutrophil caspase‐1 levels in the lungs. These findings identify that following cigarette smoke exposure, Aim2 is important for anti‐Ly6G–mediated depletion of neutrophils, suppression of neutrophil recruitment and mediates activation of caspase‐1 in neutrophils.
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.JAIP.2022.09.029
Abstract: Emerging evidence suggests that aging affects asthma outcomes, but the mechanism remains largely unexplored. To explore age-related clinical, inflammatory characteristics, phenotypes and treatment response in asthma. This study was a prospective cohort study of asthmatic patients with a 12-month follow-up period in a real-word setting. Clinical, inflammatory and phenotypic characteristics, future risk of exacerbations, and treatment response were assessed across different ages (young: 18-39 years middle-aged: 40-64 years elderly: ≥ 65 years). In comparison with young (n = 106) and middle-aged (n = 179) asthmatics, elderly asthmatics (n = 55) had worse airway obstruction, more comorbidities including COPD and diabetes, less atopy, lower levels of IgE and F This study supports that asthma in the elderly represents a specific phenotype and indicates that aging can influence asthma in terms of clinical, inflammatory characteristics, exacerbations, and treatment response.
Publisher: Frontiers Media SA
Date: 15-06-2022
DOI: 10.3389/FIMMU.2022.913044
Abstract: Long term e-cigarette vaping induces inflammation, which is largely nicotine independent. High-fat diet (HFD) consumption is anoter cause of systemic low-grade inflammation. The likelihood of using e-cigarettes as a weight control strategy is concomitant with the increase in obesity. In Australia, only nicotine-free e-fluid is legal for sale. Therefore, this study aimed to investigate how nicotine-free e-cigarette vapour exposure affects inflammatory responses in mice with long term HFD consumption. Mice were fed a HFD for 16 weeks, while in the last 6 weeks, half of the chow and HFD groups were exposed to nicotine-free e-vapour, while the other half to ambient air. Serum, lung, liver and epididymal fat were collected to measure inflammatory markers. While both e-vapour exposure and HFD consumption independently increased serum IFN-γ, CX3CL1, IL-10, CCL20, CCL12, and CCL5 levels, the levels of IFN-γ, CX3CL1, and IL-10 were higher in mice exposed to e-vapour than HFD. The mRNA expression pattern in the epididymal fat mirrors that in the serum, suggesting the circulating inflammatory response to e-vapour is from the fat tissue. Of the upregulated cytokines in serum, none were found to change in the lungs. The anti-inflammatory cytokine IL-10 was increased by combining e-vapour and HFD in the liver. We conclude that short-term nicotine-free e-vapour is more potent than long term HFD consumption in causing systemic inflammation. Future studies will be needed to examine the long-term health impact of nicotine-free e-cigarettes.
Publisher: Public Library of Science (PLoS)
Date: 05-12-2013
Publisher: Oxford University Press (OUP)
Date: 2008
DOI: 10.1086/523000
Abstract: We have developed a mask s ler for exhaled respiratory viruses. Among a group of 9 patients with cold symptoms who had virus-positive nasal mucus specimens, as analyzed by multiplexed polymerase chain reaction, virus-positive mask s les were obtained after coughing (20 times), talking (20 min), or breathing (20 min) from 6, 5, and 3 patients, respectively.
Publisher: Elsevier BV
Date: 03-2011
Publisher: Future Medicine Ltd
Date: 04-2021
Publisher: Springer Science and Business Media LLC
Date: 04-2021
DOI: 10.1038/S41591-021-01289-7
Abstract: Bronchiectasis, a progressive chronic airway disease, is characterized by microbial colonization and infection. We present an approach to the multi-biome that integrates bacterial, viral and fungal communities in bronchiectasis through weighted similarity network fusion ( integrative-microbiomics.ntu.edu.sg ). Patients at greatest risk of exacerbation have less complex microbial co-occurrence networks, reduced ersity and a higher degree of antagonistic interactions in their airway microbiome. Furthermore, longitudinal interactome dynamics reveals microbial antagonism during exacerbation, which resolves following treatment in an otherwise stable multi-biome. Assessment of the Pseudomonas interactome shows that interaction networks, rather than abundance alone, are associated with exacerbation risk, and that incorporation of microbial interaction data improves clinical prediction models. Shotgun metagenomic sequencing of an independent cohort validated the multi-biome interactions detected in targeted analysis and confirmed the association with exacerbation. Integrative microbiomics captures microbial interactions to determine exacerbation risk, which cannot be appreciated by the study of a single microbial group. Antibiotic strategies probably target the interaction networks rather than in idual microbes, providing a fresh approach to the understanding of respiratory infection.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.EJPHAR.2022.175173
Abstract: Advances in biotechnology have led to improving human health with number of novel approaches to mitigate life-threatening diseases such as human immunodeficiency virus (HIV) infection, cancer, and neurodegenerative diseases. In the case of HIV, the damage caused by the retrovirus to the immune system leads to opportunistic infection as well as an elevated risk of autoimmune disease and cancer. Furthermore, clinical symptoms associated with the virus itself may arise. Antiretroviral drug therapy using reverse transcriptase inhibitors, protease inhibitors, fusion inhibitor, chemokine receptor 5 antagonist and integrase strand transfer inhibitors have shown promising results in treating HIV infection and available in market in the form of various dosage forms. However, they are unable to completely cure the disease because of complexity in pathogenesis of HIV. In addition, these drugs have some limitations of poor solubility, permeability or, poor receptor binding capacity. To overcome these drawbacks, many novel drug delivery systems for the drugs belonging to above mentioned categories have been developed. The possibility of treating HIV infection using CRISPR-Cas9 gene editing has been found in 2015. This provided a new area of research to the scientists who are working towards alternative treatment strategies for HIV infections. The present article describes about various treatment strategies used to treat HIV infections with special emphasis on the role of CRISPR/Cas9 gene-based technology. The potential benefits of specific epigenetic modification in the c-c chemokine receptor 5 gene (CCR5) via various delivery methods are also highlighted.
Publisher: Oceanside Publications Inc.
Date: 14-09-2021
DOI: 10.2500/AAP.2021.42.210052
Abstract: Background: Symptomatic asthma and rhinitis negatively impact patients' work productivity and activity. However, little is known about the potential interaction effect of both asthma and rhinitis control on work productivity and activity impairment. Objective: This study aimed to explore whether there are interaction effects of asthma and rhinitis control on work productivity and activity impairment in patients with asthma and with rhinitis. Methods: A total of 206 adult patients were prospectively recruited and were ided into four groups: both poorly controlled (BPC) n = 53), poorly controlled asthma (PCA) with controlled rhinitis (CR) (n = 38), well controlled asthma with uncontrolled rhinitis (n = 43), and both well controlled (BWC) (n = 72) based on the symptom control status of asthma and rhinitis. Work productivity loss and activity impairment, asthma control, and rhinitis control were assessed by using work productivity and activity impairment questionnaire: general health, the asthma control test, and the rhinitis control assessment test, respectively. General linear regression models were used to study the contribution of asthma control, rhinitis control, and the interaction effect on work productivity and activity impairment. Results: Work productivity loss was most frequently reported in patients in the BPC group. Compared with the patients in the BWC group, the patients in the PCA-CR group had significantly higher activity impairment and worse asthma-related quality of life (both p 0.001). There were significant interaction effects of asthma and rhinitis control, which accounted for the increase in presenteeism, work productivity loss, and activity impairment (all p 0.001). Although differences in absenteeism were not significant among the groups, there was a significant interaction effect of control levels accounted for absenteeism (p = 0.035). Conclusion: Distinct interaction effects of asthma and rhinitis control reflected a link between upper and lower airways, which indicated that rhinitis control and the interaction effects of asthma and rhinitis control cannot be neglected during asthma management.
Publisher: Springer Science and Business Media LLC
Date: 22-05-2018
Publisher: MDPI AG
Date: 15-11-2022
Abstract: Objective: Particulate matter (PM) with a diameter of 2.5 μm or less (PM2.5) can cross the blood-placental barrier causing adverse foetal outcomes. However, the impact of maternal exposure to low-levels of PM2.5 on liver health and the metabolic profile is unclear. This study aimed to investigate hepatic responses to long-term gestational low-dose PM2.5 exposure, and whether the removal of PM after conception can prevent such effects. Method: Female Balb/c mice (8 weeks) were exposed to PM2.5 (5 μg/day) for 6 weeks prior to mating, during gestation and lactation to model living in a polluted environment (PM group). In a sub-group, PM2.5 exposure was stopped post-conception to model mothers moving to areas with clean air (pre-gestation, Pre) group. Livers were studied in 13-week old offspring. Results: Female offspring in both PM and Pre groups had increased liver triglyceride and glycogen levels, glucose intolerance, but reduced serum insulin and insulin resistance. Male offspring from only the Pre group had increased liver and serum triglycerides, increased liver glycogen, glucose intolerance and higher fasting glucose level. Markers of oxidative stress and inflammation were increased in females from PM and Pre groups. There was also a significant sex difference in the hepatic response to PM2.5 with differential changes in several metabolic markers identified by proteomic analysis. Conclusions: Maternal PM exposure exerted sex-dependent effects on liver health with more severe impacts on females. The removal of PM2.5 during gestation provided limited protection in the offspring’s metabolism regardless of sex.
Publisher: American Physiological Society
Date: 09-2019
DOI: 10.1152/AJPLUNG.00232.2019
Abstract: Air pollution is a ubiquitous problem and comprises gaseous and particulate matter (PM). Epidemiological studies have clearly shown that exposure to PM is associated with impaired lung function and the development of lung diseases, such as chronic obstructive pulmonary disease and asthma. To understand the mechanisms involved, animal models are often used. However, the majority of such models represent high levels of exposure and are not representative of the exposure levels in less polluted countries, such as Australia. Therefore, in this study, we aimed to determine whether low dose PM 10 exposure has any detrimental effect on the lungs. Mice were intranasally exposed to saline or traffic-related PM 10 (1μg or 5μg/day) for 3 wk. Bronchoalveolar lavage (BAL) and lung tissue were analyzed. PM 10 at 1 μg did not significantly affect inflammatory and mitochondrial markers. At 5 μg, PM 10 exposure increased lymphocytes and macrophages in BAL fluid. Increased NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and IL-1β production occurred following PM 10 exposure. PM 10 (5 μg) exposure reduced mitochondrial antioxidant manganese superoxide (antioxidant defense system) and mitochondrial fusion marker (OPA-1), while it increased fission marker (Drp-1). Autophagy marker light-chain 3 microtubule-associated protein (LC3)-II and phosphorylated-AMPK were reduced, and apoptosis marker (caspase 3) was increased. No significant change of remodeling markers was observed. In conclusion, a subchronic low-level exposure to PM can have an adverse effect on lung health, which should be taken into consideration for the planning of roads and residential buildings.
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.
Publisher: American Thoracic Society
Date: 15-12-2016
Publisher: Springer Science and Business Media LLC
Date: 17-09-2018
Publisher: Wiley
Date: 05-08-2011
Publisher: Springer Science and Business Media LLC
Date: 25-07-2018
DOI: 10.1038/S41598-018-29430-6
Abstract: There is a need for pharmaceutical agents that can reduce neuronal loss and improve functional deficits following traumatic brain injury (TBI). Previous research suggests that oxidative stress and mitochondrial dysfunction play a major role in neuronal damage after TBI. Therefore, this study aimed to investigate two drugs known to have antioxidant effects, L-carnitine and exendin-4, in rats with moderate contusive TBI. L-carnitine (1.5 mM in drinking water) or exendin-4 (15 µg/kg/day, ip) were given immediately after the injury for 2 weeks. Neurological function and brain histology were examined (24 h and 6 weeks post injury). The rats with TBI showed slight sensory, motor and memory functional deficits at 24 h, but recovered by 6 weeks. Both treatments improved sensory and motor functions at 24 h, while only exendin-4 improved memory. Both treatments reduced cortical contusion at 24 h and 6 weeks, however neither affected gliosis and inflammatory cell activation. Oxidative stress was alleviated and mitochondrial reactive oxygen species was reduced by both treatments, however only mitochondrial functional marker protein transporter translocase of outer membrane 20 was increased at 24 h post injury. In conclusion, L-carnitine and exendin-4 treatments immediately after TBI can improve neurological functional outcome and tissue integrity by reducing oxidative stress.
Publisher: Cold Spring Harbor Laboratory
Date: 31-08-2023
DOI: 10.1101/2023.08.30.555286
Abstract: Cellular senescence has been recognized to play a role in COPD pathophysiology. Non-aerosolized E-liquid treatment of a lung fibroblast foetal cell line resulted in cellular senescence induction, but this has not been assessed using E-vapour exposure and using primary lung fibroblasts. Therefore, we investigated whether E-vapour exposure induces cellular senescence in primary human lung fibroblasts and whether this affects their tissue repair function. Primary human lung fibroblasts were stimulated with E-cigarette vapour extracts, and cigarette smoke extract (CSE) and Paraquat (PQ) as positive controls. IL-8 secretion was measured to confirm a stimulatory response. Multiple senescence markers (p16, p21, SA-β-gal, and proliferation) were assessed and the tissue repair function was assessed using a scratch assay. Finally, we tried to validate our findings in an E-cigarette-exposed mouse model. Upon stimulation with CSE, PQ, and E-vapour extracts, cellular senescence was induced, which seemed dose-dependent and nicotine-independent. E-vapour-induced senescence resulted in an impaired tissue repair function. No significant difference was observed in the E-cigarette-exposed mouse model. In this study, we identify E-cigarette vapours potential to induce cellular senescence in primary human lung fibroblasts and that this affects their tissue repair function, which further adds to the identified risks of E-cigarette use.
Publisher: American Society for Clinical Investigation
Date: 08-04-2021
Publisher: American Physiological Society
Date: 2021
DOI: 10.1152/AJPLUNG.00273.2020
Abstract: Tobacco smoke has harmful effects on a multiorgan level. Exposure to smoke, whether in utero or environmental, significantly increases susceptibility. This susceptibility has been identified to be ergent between males and females. However, there remains a distinct lack of thorough research into the relationship between sex and exposure to tobacco. Females tend to generate a more significant response than males during adulthood exposure. The intrauterine environment is meticulously controlled, and exposure to tobacco presents a significant factor that contributes to poor health outcomes and susceptibility later in life. Analysis of these effects in relation to the sex of the offspring is yet to be holistically reviewed and summarized. In this review, we will delineate the time-dependent relationship between tobacco smoke exposure and sex-specific disease susceptibility. We further outline possible biological mechanisms that may contribute to the identified pattern.
Publisher: European Respiratory Society
Date: 09-2015
Publisher: Wiley
Date: 21-12-2015
DOI: 10.1111/ALL.12810
Abstract: IL-17A plays an important role in respiratory disease and is a known regulator of pulmonary inflammation and immunity. Recent studies have linked IL-17A with exacerbation in asthma and COPD. We have shown that the enzyme cyclooxygenase-2 (COX-2) and its prostanoid products, prostaglandin E2 (PGE2 ) in particular, are key contributors in in vitro models of infectious exacerbation however, the impact of IL-17A was not known. We address this herein and show that IL-17A induces a robust and sustained upregulation of COX-2 protein and PGE2 secretion from airway smooth muscle (ASM) cells. COX-2 can be regulated at transcriptional, post-transcriptional and/or post-translational levels. We have elucidated the underlying molecular mechanisms responsible for the sustained upregulation of TNF-α-induced COX-2 by IL-17A in ASM cells and show that is not via increased COX-2 gene expression. Instead, TNF-α-induced COX-2 upregulation is subject to regulation by the proteasome, and IL-17A acts to increase TNF-α-induced COX-2 protein stability as confirmed by cycloheximide chase experiments. In this way, IL-17A acts to lify the COX-2-mediated effects of TNF-α and greatly enhances PGE2 secretion from ASM cells. As PGE2 is a multifunctional prostanoid with erse roles in respiratory disease, our studies demonstrate a novel function for IL-17A in airway inflammation by showing for the first time that IL-17A impacts on the COX-2/PGE2 pathway, molecules known to contribute to disease exacerbation.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.ECOENV.2022.113589
Abstract: Air pollution remains one of the major health threats around the world. Compared to adults, foetuses and infants are more vulnerable to the effects of environmental toxins. Maternal exposure to air pollution causes several adverse birth outcomes and may lead to life-long health consequences. Given that a healthy intrauterine environment is a critical factor for supporting normal foetal brain development, there is a need to understand how prenatal exposure to air pollution affects brain health and results in neurological dysfunction. This review summarised the current knowledge on the adverse effects of prenatal air pollution exposure on early life neurodevelopment and subsequent impairment of cognition and behaviour in childhood, as well as the potential of early-onset neurodegeneration. While inflammation, oxidative stress, and endoplasmic reticulum are closely involved in the physiological response, sex differences also occur. In general, males are more susceptible than females to the adverse effect of in-utero air pollution exposure. Considering the evidence provided in this review and the rising concerns of global air pollution, any efforts to reduce pollutant emission or exposure will be protective for the next generation.
Publisher: Hindawi Limited
Date: 17-05-2012
DOI: 10.1155/2012/968039
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 03-2003
Abstract: Neutrophils and mononuclear cells are implicated in the pathogenesis of several inflammatory conditions including chronic obstructive pulmonary disease (COPD). Neutrophil-derived serine proteases, such as cathepsin G (CG) and neutrophil elastase (NE), may interact with mononuclear cells via protease-activated receptors (PARs) which are seven-transmembrane G protein-coupled receptors activated by proteolytic cleavage of the extracellular N-terminus, and which, on activation, induce the release of several mediators and cytokines. We determined whether CG and NE could affect PAR-1 expression and function in mononuclear cells. Human blood mononuclear cells were isolated from 20 healthy donors. Surface and intracellular receptor expression and calcium mobilisation (using the calcium chelator, FLUO3-AM) were studied by fluorescence-assisted cell sorting (FACS analysis). Positive controls, i.e. thrombin (0.1-100 mU/ml) and the PAR-1-activating peptide SFLLRN (100 microM) induced a rapid and transient intemalisation of PAR-1 in monocytes and lymphocytes. CG but not NE had a similar effect. By contrast, in monocytes intracellular calcium mobilisation was induced by thrombin and SFLLRN but not by CG and NE. Thus, CG can induce intracellular PAR-1 sequestration without activation of the receptor, and may act as an antagonist and prevent subsequent activation of PAR-1 in mononuclear cells. These findings may be of relevance to the pathogenesis of COPD.
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.
Publisher: Elsevier BV
Date: 07-2023
Publisher: BMJ
Date: 03-12-2020
DOI: 10.1136/THORAXJNL-2020-215114
Abstract: COPD-derived fibroblasts have increased cellular senescence. Senescent cell accumulation can induce tissue dysfunction by their senescence-associated secretory phenotype (SASP). We aimed to determine the SASP of senescent fibroblasts and COPD-derived lung fibroblasts, including severe, early-onset (SEO)-COPD. SASP protein secretion was measured after paraquat-induced senescence in lung fibroblasts using Olink Proteomics and compared between (SEO-)COPD-derived and control-derived fibroblasts. We identified 124 SASP proteins of senescent lung fibroblasts, of which 42 were secreted at higher levels by COPD-derived fibroblasts and 35 by SEO-COPD-derived fibroblasts compared with controls. Interestingly, the (SEO-)COPD-associated SASP included proteins involved in chronic inflammation, which may contribute to (SEO-)COPD pathogenesis.
Publisher: American Physiological Society
Date: 10-2021
DOI: 10.1152/AJPLUNG.00138.2021
Abstract: The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also h ers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.
Publisher: Elsevier BV
Date: 11-2017
Publisher: IOP Publishing
Date: 26-09-2016
DOI: 10.1088/1752-7155/10/4/046002
Abstract: Respiratory viruses are very common in the community and contribute to the burden of illness for patients with chronic respiratory diseases, including acute exacerbations. Traditional s ling methods are invasive and problematic to repeat. Accordingly, we explored whether respiratory viruses could be isolated from disposable spirometry filters and whether detection of viruses in this context represented presence in the upper or lower respiratory tract. Discovery (n = 53) and validation (n = 49) cohorts were recruited from a hospital outpatient department during two different time periods. Spirometry mouthpiece filters were collected from all participants. Respiratory secretions were s led from the upper and lower respiratory tract by nasal washing (NW), sputum, and bronchoalveolar lavage (BAL). All s les were examined using RT-PCR to identify a panel of respiratory viruses (rhinovirus, respiratory syncytial virus, influenza A, influenza B, parainfluenza virus 1, 2 & 3, and human metapneumovirus). Rhinovirus was quantified using qPCR. Paired filter-NW s les (n = 29), filter-sputum s les (n = 24), filter-BAL s les (n = 39) and filter-NW-BAL s les (n = 10) provided a range of comparisons. At least one virus was detected in any s le in 85% of participants in the discovery cohort versus 45% in the validation cohort. Overall, 72% of viruses identified in the paired comparator method matched those detected in spirometry filters. There was a high correlation between viruses identified in spirometry filters compared with viruses identified in both the upper and lower respiratory tract using traditional s ling methods. Our results suggest that examination of spirometry filters may be a novel and inexpensive s ling method for the presence of respiratory viruses in exhaled breath.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Bentham Science Publishers Ltd.
Date: 27-03-2020
DOI: 10.2174/0929867325666180927100120
Abstract: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play crucial and often opposing regulatory roles in health and in pathological conditions. n-3 and n-6 PUFA undergo biotransformation to parallel series of lipid mediators that are potent modulators of many cellular processes. A wide range of biological actions have been attributed to lipid mediators derived from n-6 PUFA, and these mediators have served as lead compounds in the development of numerous clinically approved drugs, including latanoprost (Xalatan: Pfizer), which is listed on the WHO Model List of Essential Medicines. n-3 PUFA-derived mediators have received less attention, in part because early studies suggested that n-3 PUFA act simply as competitive substrates for biotransformation enzymes and decrease the formation of n-6 PUFA-derived lipid mediators. However, more recent studies suggest that n-3 PUFA-derived mediators are biologically important in their own right. It is now emerging that many n-3 PUFA-derived lipid mediators have potent and erse activities that are distinct from their n-6 counterparts. These findings provide new opportunities for drug discovery. Herein, we review the biosynthesis of n-3 PUFA-derived lipid mediators and highlight their biological actions that may be exploited for drug development. Lastly, we provide ex les of medicinal chemistry research that has utilized n-3 PUFA-derived lipid mediators as novel lead compounds in drug design.
Publisher: American Physiological Society
Date: 2019
DOI: 10.1152/AJPLUNG.00306.2018
Abstract: Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01–25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10–25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.
Publisher: Springer Science and Business Media LLC
Date: 1999
Abstract: Calcified microspheres, about 1 microm in diameter, appear at sites of bone formation where they invest the collagenous matrix, become confluent and disappear. Evidence that the particle boundaries are not lost with compaction but merely deformed is supported in section by the granular histochemical staining of the inorganic phase for bone salt, lipid, fibronectin and acid phosphatase in osteomalacic, acid-etched and normal human bone. Their persistence as discrete objects is confirmed by the application of methods for their isolation from the collagenous matrix of immature mouse calvarium and mature bovine femur. Five methods have been used to extract them and include (i) biochemical, (ii) chemical, (iii) mechanical, (iv) pyrogenous and (v) biological separation. Under the optical microscope, all isolates consisted of similar discrete objects and bridged assemblies, whose birefringence varied with treatment. After decalcification, their organic 'ghosts' remained. Each isolated microsphere had a complex substructure of clusters of non-collagenous calcified filaments surrounding a less dense centre. The filaments were 5 nm in diameter with a 5 nm periodicity and regular fine interfilamentous connections. It is concluded that the microspheres are independent, complex, pervasive and central to the containment (i.e. packaging) of calcium phosphate in bone. Their extraction will enable further analysis.
Publisher: Elsevier BV
Date: 10-2023
Publisher: MDPI AG
Date: 08-2018
Abstract: Maternal smoking during pregnancy leads to gestational complications and organ disorders in the offspring. As nicotine replacement therapy is often ineffective for smoking cessation, pregnant women turn to alternatives such as heat-not-burn tobacco and e-cigarettes. Recently, the popularly of e-cigarettes has been increasing especially among the youth and pregnant women, mainly due to the advertisements claiming their safety. This has even led to some clinicians recommending their use during pregnancy. E-cigarettes heat e-liquid to produce an aerosol (e-vapor), delivering flavorings and nicotine to the user. However, e-vapor also contains toxins such as formaldehyde along with heavy metals and carcinogenic nitrosamines. In addition, specific flavoring compounds such as diacetyl can be toxic themselves or decompose into toxic compounds such as benzaldehydes. These compounds can induce toxicity, inflammation and oxidative stress in the mothers and can accumulate in the developing fetus, affecting intrauterine development. Recent animal studies suggest that maternal e-vapor exposure during pregnancy could cause respiratory and neurological disorders in the offspring. This review will examine the available literature to shed light on the current understanding of this problem-to-be from lessons learned in animal models.
Publisher: Frontiers Media SA
Date: 07-2021
DOI: 10.3389/FPHYS.2021.700246
Abstract: Objectives: Maternal cigarette smoke exposure (SE) causes intrauterine undernutrition, resulting in increased risk for metabolic disorders and type 2 diabetes in the offspring without sex differences. L-leucine supplementation has been shown to reduce body weight and improve glucose metabolism in both obese animals and humans. In this study, we aimed to determine whether postnatal L-leucine supplementation in female offspring can ameliorate the detrimental impact of maternal SE. Methods: Female Balb/c mice (6-week) were exposed to cigarette smoke (SE, 2 cigarettes/day) prior to mating for 5 weeks until the pups weaned. Sham dams were exposed to air during the same period. Half of the female offspring from the SE and SHAM dams were supplied with L-leucine via drinking water (1.5% w/w) after weaning (21-day) for 10 weeks and sacrificed at 13 weeks (adulthood). Results: Maternal SE during pregnancy resulted in smaller body weight and glucose intolerance in the offspring. L-leucine supplement in Sham offspring reduced body weight, fat mass, and fasting blood glucose levels compared with their untreated littermates however somatic growth was not changed. L-leucine supplement in SE offspring improved glucose tolerance and reduced fat mass compared with untreated littermates. Conclusions: Postnatal L-leucine supplement could reduce fat accumulation and ameliorate glucose metabolic disorder caused by maternal SE. The application of leucine may provide a potential strategy for reducing metabolic disorders in offspring from mothers who continued to smoke during pregnancy.
Publisher: European Respiratory Society (ERS)
Date: 29-07-2021
DOI: 10.1183/13993003.03969-2020
Abstract: Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3). To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response. The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (paediatric cases/controls: n=134/n=35 adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (OVA), challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using the Asthma Control Test. Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5). C4Ma3 levels depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.MITO.2022.09.003
Abstract: Mitochondria are one of the basic essential components for eukaryotic life survival. It is also the source of respiratory ATP. Recently published studies have demonstrated that mitochondria may have more roles to play aside from energy production. There is an increasing body of evidence which suggest that mitochondrial activities involved in normal and pathological states contribute to significant impact to the lung airway morphology and epithelial function in respiratory diseases such as asthma, COPD, and lung cancer. This review summarizes the pathophysiological pathways involved in asthma, COPD, lung cancer and highlights potential treatment strategies that target the malfunctioning mitochondria in such ailments. Mitochondria are responsive to environmental stimuli such as infection, tobacco smoke, and inflammation, which are essential in the pathogenesis of respiratory diseases. They may affect mitochondrial shape, protein production and ultimately cause dysfunction. The impairment of mitochondrial function has downstream impact on the cytosolic components, calcium control, response towards oxidative stress, regulation of genes and proteins and metabolic activities. Several novel compounds and alternative medicines that target mitochondria in asthma and chronic lung diseases have been discussed here. Moreover, mitochondrial enzymes or proteins that may serve as excellent therapeutic targets in COPD are also covered. The role of mitochondria in respiratory diseases is gaining much attention and mitochondria-based treatment strategies and personalized medicine targeting the mitochondria may materialize in the near future. Nevertheless, more in-depth studies are urgently needed to validate the advantages and efficacy of drugs that affect mitochondria in pathological states.
Publisher: Wiley
Date: 15-09-2020
DOI: 10.1111/ALL.14549
Publisher: American Thoracic Society
Date: 2012
Publisher: Elsevier BV
Date: 06-2021
Publisher: Elsevier BV
Date: 09-2023
Publisher: MDPI AG
Date: 16-09-2022
DOI: 10.3390/NU14183828
Abstract: Chronic inflammation of the respiratory tract is one of the most concerning public health issues, as it can lead to chronic respiratory diseases (CRDs), some of which are more detrimental than others. Chronic respiratory diseases include chronic obstructive pulmonary disease (COPD), asthma, lung cancer, and pulmonary fibrosis. The conventional drug therapies for the management and treatment of CRDs only address the symptoms and fail to reverse or recover the chronic-inflammation-mediated structural and functional damage of the respiratory tract. In addition, the low efficacy and adverse effects of these drugs have directed the attention of researchers towards nutraceuticals in search of potential treatment strategies that can not only ameliorate CRD symptoms but also can repair and reverse inflammatory damage. Hence, there is a growing interest toward investigating the medicinal benefits of nutraceuticals, such as rutin, curcumin, zerumbone, and others. Nutraceuticals carry many nutritional and therapeutic properties, including anti-inflammatory, antioxidant, anticancer, antidiabetic, and anti-obesity properties, and usually do not have as many adverse effects, as they are naturally sourced. Recently, the use of nanoparticles has also been increasingly studied for the nano drug delivery of these nutraceuticals. The discrete size of nanoparticles holds great potential for the level of permeability that can be achieved when transporting these nutraceutical compounds. This review is aimed to provide an understanding of the use of nutraceuticals in combination with nanoparticles against CRDs and their mechanisms involved in slowing down or reversing the progression of CRDs by inhibiting pro-inflammatory signaling pathways.
Publisher: Wiley
Date: 03-09-2020
DOI: 10.1111/RESP.13688
Abstract: Fixed airflow obstruction (FAO) in asthma occurs despite optimal inhaled treatment and no smoking history, and remains a significant problem, particularly with increasing age and duration of asthma. Increased lung compliance and loss of lung elastic recoil has been observed in older people with asthma, but their link to FAO has not been established. We determined the relationship between abnormal lung elasticity and airflow obstruction in asthma. Non-smoking asthmatic subjects aged >40 years, treated with 2 months of high-dose inhaled corticosteroid/long-acting beta-agonist (ICS/LABA), had FAO measured by spirometry, and respiratory system resistance at 5 Hz (Rrs Eighteen subjects (11 males mean ± SD age: 64 ± 8 years, asthma duration: 39 ± 22 years) had moderate FAO measured by spirometry ((mean ± SD z-score) post-bronchodilator FEV Increased lung compliance and loss of elastic recoil relate to airflow obstruction in older non-smoking asthmatic subjects, independent of ageing. Thus, structural lung tissue changes may contribute to persistent, steroid-resistant airflow obstruction. ACTRN126150000985583 at anzctr.org.au (UTN: U1111-1156-2795).
Publisher: Oxford University Press (OUP)
Date: 04-06-2021
DOI: 10.1093/BFGP/ELAB027
Abstract: Messenger RNA (mRNA) vaccines have recently emerged as a new type of vaccine technology, showing strong potential to combat the COVID-19 pandemic. In addition to SARS-CoV-2 which caused the pandemic, mRNA vaccines have been developed and tested to prevent infectious diseases caused by other viruses such as Zika virus, the dengue virus, the respiratory syncytial virus, influenza H7N9 and Flavivirus. Interestingly, mRNA vaccines may also be useful for preventing non-infectious diseases such as diabetes and cancer. This review summarises the current progresses of mRNA vaccines designed for a range of diseases including COVID-19. As epitope study is a primary component in the in silico design of mRNA vaccines, we also survey on advanced bioinformatics and machine learning algorithms which have been used for epitope prediction, and review on user-friendly software tools available for this purpose. Finally, we discuss some of the unanswered concerns about mRNA vaccines, such as unknown long-term side effects, and present with our perspectives on future developments in this exciting area.
Publisher: Informa UK Limited
Date: 03-2009
DOI: 10.2147/JAA.S4016
Publisher: American Thoracic Society
Date: 15-01-2010
Publisher: Frontiers Media SA
Date: 16-03-2021
Abstract: Objectives: Maternal smoking causes fetal underdevelopment and results in births which are small for gestation age due to intrauterine undernutrition, leading to various metabolic disorders in adulthood. Furthermore, postnatal high fat diet (HFD) consumption is also a potent obesogenic factor, which can interact with maternal smoking. In this study, we aimed to determine whether maternal HFD consumption during pregnancy can reverse the adverse impact of maternal smoking and change the response to postnatal HFD consumption. Methods: Female mice were exposed to cigarette smoke (SE, 2 cigarettes/day) or sham exposed for 5 weeks before mating, with half of the SE dams fed HFD (43% fat, SE+HFD). The same treatment continued throughout gestation and lactation. Male offspring from each maternal group were fed the same HFD or chow after weaning and sacrificed at 13 weeks. Results: Maternal SE alone increased body weight and fat mass in HFD-fed offspring, while SE+HFD offspring showed the highest energy intake and glucose metabolic disorder in adulthood. In addition, postnatal HFD increased the body weight and aggravated the metabolic disorder caused by maternal SE and SE+HFD. Conclusions: Maternal HFD consumption could not ameliorate the adverse effect of maternal SE but exaggerate metabolic disorders in adult offspring. Smoking cessation and a healthy diet are needed during pregnancy to optimize the health outcome in the offspring.
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.
Publisher: Wiley
Date: 28-08-2018
DOI: 10.1111/CEA.13236
Abstract: Asthma is a chronic inflammatory disease with structural changes present. Burgess and colleagues recently found tumstatin markedly reduced in adult asthmatic lung tissue compared with nonasthmatics. ECM fragments such as tumstatin are named matrikines and act independently of the parent molecule. The role of Col IV matrikines in neutrophil inflammation (eg. exacerbation in asthma) has not been investigated to date. Severe adult asthma phenotypes are dominated by neutrophilic inflammation and show a high frequency of severe exacerbations. This study sought to investigate the role of a novel active region within tumstatin (CP17) and its implication in neutrophil inflammatory responses related to asthma exacerbation. For reactive oxygen production, isolated neutrophils were preincubated with peptides or vehicle for 1 hour and stimulated (PMA). Luminescence signal was recorded (integration over 10 seconds) for 1.5 hours. Neutrophil migration was performed according to the SiMA protocol. Mice were sensitized to OVA/Alumn by intraperitoneal (i.p.) injections. Mice were then treated with CP17, vehicle (PBS) or scrambled peptide (SP17) after OVA exposure (days 27 and 28, polyI:C stimulation). All animals were killed on day 29 with lung function measurement, histology and lavage. CP17 decreased total ROS production rate to 52.44% (0.5 μmol/L, P < 0.05 vs SP17), reduced the in vitro directionality (vs SP17, P = 1 × 10 CP17 reduced the ROS production rate, migrational speed and selectively inhibited neutrophil accumulation in the lung interstitium and lumen. CP17 may serve as a potential precursor for drug development to combat overwhelming neutrophil inflammation.
Publisher: Public Library of Science (PLoS)
Date: 18-05-2016
Publisher: Frontiers Media SA
Date: 04-11-2021
DOI: 10.3389/FPHYS.2021.755124
Abstract: Tobacco smoking increases the risk of metabolic disorders due to the combination of harmful chemicals, whereas pure nicotine can improve glucose tolerance. E-cigarette vapour contains nicotine and some of the harmful chemicals found in cigarette smoke at lower levels. To investigate how e-vapour affects metabolic profiles, male Balb/c mice were exposed to a high-fat diet (HFD, 43% fat, 20kJ/g) for 16weeks, and e-vapour in the last 6weeks. HFD alone doubled fat mass and caused dyslipidaemia and glucose intolerance. E-vapour reduced fat mass in HFD-fed mice only nicotine-containing e-vapour improved glucose tolerance. In chow-fed mice, e-vapour increased lipid content in both blood and liver. Changes in liver metabolic markers may be adaptive responses rather than causal. Future studies can investigate how e-vapour differentially affects metabolic profiles with different diets.
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.JACI.2006.05.019
Abstract: Airway smooth muscle (ASM) cells may contribute to airway remodeling through the release of growth factors, cytokines, and extracellular matrix (ECM) proteins. The effect of current asthma therapies on this release is not known. We examined the effect of corticosteroids, long-acting beta(2)-agonists, and a phosphodiesterase 4 (PDE4) inhibitor on ASM-released connective tissue growth factor (CTGF), collagen I, fibronectin, versican, and IL-6. Airway smooth muscle cells from in iduals with and without asthma were stimulated with TGF-beta with or without the drugs and CTGF and ECM protein expression measured by real-time PCR, cell surface, or matrix-associated ELISA. IL-6 release was measured by ELISA. Bronchial rings from in iduals without asthma were incubated with TGF-beta with or without the drugs. Neither corticosteroids nor long-acting beta(2)-agonists reduced TGF-beta-induced CTGF, collagen I, or fibronectin in either cell type, whereas corticosteroids alone induced the expression of CTGF, collagen I, and fibronectin. These drugs did not prevent the accumulation of TGF-beta-induced proteins in bronchial rings, whereas the PDE4 inhibitor roflumilast inhibited TGF-beta-induced CTGF, collagen I, and fibronectin. In our model, current asthma therapies are not able to inhibit matrix protein deposition from ASM cells. The results of this study suggest that the PDE4 inhibitor roflumilast may have a role in regulating the ECM and therefore aspects of airway remodeling in asthma. Although current asthma therapies are effective in reducing inflammation and symptoms, reversal or prevention of structural changes contributing to remodeling may require additional therapy, which could include PDE4 inhibitors.
Publisher: European Respiratory Society (ERS)
Date: 02-2019
Publisher: Wiley
Date: 12-2012
Publisher: Springer Science and Business Media LLC
Date: 22-11-2022
DOI: 10.1186/S12890-022-02191-9
Abstract: Effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) demonstrates positive effects on stable chronic obstructive pulmonary disease (COPD). To investigate the mechanisms of ECC-BYF III on COPD rats from the aspect of airway epithelial cell senescence. COPD model rats (Sprague-Dawley rat) were treated with ECC-BYF III for 8 weeks, and the efficacy was evaluated. Cigarette smoke extract (CSE)-induced senescence model of airway epithelial cells was treated with ECC-BYF III, and related enzymes and proteins involved in oxidative stress and mitophagy were detected. ECC-BYF III markedly rescued pulmonary function and histopathological changes, which might be associated with the amelioration of lung senescence, including the reduction of malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-9 levels, increase of the level in total superoxide dismutase (T-SOD), and decease in the p21 level in the airways. Furthermore, ECC-BYF III suppressed p16 and p21 expressions and senescence-associated β-galactosidase (SA-β-Gal) in CSE-induced airway epithelial cells. Moreover, ECC-BYF III upregulated mitophagy-related proteins, including the co-localizations of TOM20 and LC3B, PINK1 and PARK2, and improved mitochondrial function by upregulating mitochondrial mitofusin (MFN)2 and reducing dynamin-related protein 1 (DRP1) expression. ECC-BYF III enhanced the activities of T-SOD and GSH-PX by up-regulating NRF2, thus inhibiting oxidative stress. After intervention with NRF2 inhibitor, the regulation effects of ECC-BYF III on oxidative stress, mitophagy and senescence in airway epithelial cells were significantly suppressed. ECC-BYF III exerts beneficial effects on COPD rats by ameliorating airway epithelial cell senescence, which is mediated by inhibiting oxidative stress and subsequently enhancing mitophagy through the activation of NRF2 signaling.
Publisher: Elsevier BV
Date: 09-2020
Publisher: F1000 Research Ltd
Date: 11-06-2018
DOI: 10.12688/F1000RESEARCH.11236.2
Abstract: In the past decade, an emerging process named “autophagy” has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease.
Publisher: F1000 Research Ltd
Date: 03-04-2017
DOI: 10.12688/F1000RESEARCH.11236.1
Abstract: In the past decade, an emerging process named “autophagy” has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease.
Publisher: American Society for Microbiology
Date: 11-2014
DOI: 10.1128/IAI.01800-14
Abstract: Plasmodium sporozoites develop within oocysts in the mosquito midgut wall and then migrate to the salivary glands. After transmission, they embark on a complex journey to the mammalian liver, where they infect hepatocytes. Proteins on the sporozoite surface likely mediate multiple steps of this journey, yet only a few sporozoite surface proteins have been described. Here, we characterize a novel, conserved sporozoite surface protein (SSP3) in the rodent malaria parasite Plasmodium yoelii . SSP3 is a putative type I transmembrane protein unique to Plasmodium . By using epitope tagging and SSP3-specific antibodies in conjunction with immunofluorescence microscopy, we showed that SSP3 is expressed in mosquito midgut oocyst sporozoites, exhibiting an intracellular localization. In sporozoites derived from the mosquito salivary glands, however, SSP3 localized predominantly to the sporozoite surface as determined by immunoelectron microscopy. However, the ectodomain of SSP3 appeared to be inaccessible to antibodies in nonpermeabilized salivary gland sporozoites. Antibody-induced shedding of the major surface protein circumsporozoite protein (CSP) exposed the SSP3 ectodomain to antibodies in some sporozoites. Targeted deletion of SSP3 adversely affected in vitro sporozoite gliding motility, which, surprisingly, impacted neither their cell traversal capacity, host cell invasion in vitro , nor infectivity in vivo . Together, these data reveal a previously unappreciated complexity of the Plasmodium sporozoite surface proteome and the roles of surface proteins in distinct biological activities of sporozoites.
Publisher: Frontiers Media SA
Date: 27-11-2018
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.
Publisher: Begell House
Date: 2022
Publisher: American Physiological Society
Date: 04-2012
DOI: 10.1152/AJPLUNG.00167.2011
Abstract: In asthma, airway smooth muscle (ASM) chemokine secretion can induce mast cell recruitment into the airways. The functions of the mast cell chemoattractant CXCL10, and other chemokines, are regulated by binding to heparan sulphates such as syndecan-4. This study is the first demonstration that airway smooth muscle cells (ASMC) from people with and without asthma express and shed syndecan-4 under basal conditions. Syndecan-4 shedding was enhanced by stimulation for 24 h with the Th1 cytokines interleukin-1β (IL-1β) or tumor necrosis factor-α (TNF-α), but not interferon-γ (IFNγ), nor the Th2 cytokines IL-4 and IL-13. ASMC stimulation with IL-1β, TNF-α, and IFNγ (cytomix) induced the highest level of syndecan-4 shedding. Nonasthmatic and asthmatic ASM cell-associated syndecan-4 protein expression was also increased by TNF-α or cytomix at 4–8 h, with the highest levels detected in cytomix-stimulated asthmatic cells. Cell-associated syndecan-4 levels were decreased by 24 h, whereas shedding remained elevated at 24 h, consistent with newly synthesized syndecan-4 being shed. Inhibition of ASMC matrix metalloproteinase-2 did not prevent syndecan-4 shedding, whereas inhibition of ERK MAPK activation reduced shedding from cytomix-stimulated ASMC. Although ERK inhibition had no effect on syndecan-4 mRNA levels stimulated by cytomix, it did cause an increase in cell-associated syndecan-4 levels, consistent with the shedding being inhibited. In conclusion, ASMC produce and shed syndecan-4 and although this is increased by the Th1 cytokines, the MAPK ERK only regulates shedding. ASMC syndecan-4 production during Th1 inflammatory conditions may regulate chemokine activity and mast cell recruitment to the ASM in asthma.
Publisher: Wiley
Date: 26-01-2010
DOI: 10.1111/J.1440-1843.2009.01683.X
Abstract: PPARgamma levels in asthma- and non-asthma-derived airway smooth muscle cells and PPARgamma activation-induced cell proliferation were investigated. In the presence of FBS, PPARgamma levels were higher in subconfluent asthma-derived cells but lower in confluent cells compared with non-asthma-derived. However, PPARgamma activation did not alter cell proliferation. Airway remodelling involves thickening of the airway smooth muscle (ASM) bulk. Proliferation of asthma-derived ASM cells is increased in vitro, but underlying mechanisms remain unknown. Peroxisome proliferators activated receptor-gamma (PPARgamma) regulates the cell cycle. It is suggested that PPARgamma agonists have anti-inflammatory effects, which may be valuable in the treatment of asthma, but information regarding their antiproliferative properties in ASM is lacking. Although corticosteroids reduce airway inflammation, in vitro they inhibit proliferation in only non-asthma ASM cells by reducing cyclin D1. We therefore investigated the effects of mitogenic stimulation (foetal bovine serum (FBS)), and a PPARgamma ligand (ciglitazone), on PPARgamma and cyclin D1 expression and proliferation of ASM cells. In addition, we examined the effects of ciglitazone on ASM cell proliferation. We assessed PPARgamma and cyclin D1 mRNA and protein levels using quantitative PCR and immunoblotting. Cell proliferation was assessed using bromodeoxyuridine uptake. In the presence of 5% FBS, PPARgamma and cyclin D1 expression decreased over time in non-asthmatic cells but increased in asthmatic cells (compared with sub-confluent cells). FBS-induced proliferation of asthmatic cells increased at all time points, but occurred only at day 7 with non-asthmatic cells (compared with unstimulated time-matched control). Ciglitazone increased PPARgamma expression in both groups, but did not alter cell proliferation, while fluticasone increased PPARgamma protein only in asthmatic cells. Although in the presence of a mitogenic stimulus, PPARgamma was differentially expressed in asthma- and non-asthma-derived ASM its expression was not related to the increased proliferation observed in asthmatic ASM.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/219374
Abstract: Background . Respiratory infections are a major cause of asthma exacerbations where neutrophilic inflammation dominates and is associated with steroid refractory asthma. Structural airway cells in asthma differ from nonasthmatics however it is unknown if neutrophils differ. We investigated neutrophil immune responses in patients who have good ( A G o o d ) and suboptimal ( A S u b o p t ) asthma symptom control. Methods . Peripheral blood neutrophils from A G o o d (ACQ 0.75, n = 11 ), A S u b o p t (ACQ 0.75, n = 7 ), and healthy controls (HC) ( n = 9 ) were stimulated with bacterial (LPS (1 μ g/mL), fMLF (100 nM)), and viral (imiquimod (3 μ g/mL), R848 (1.5 μ g/mL), and poly I:C (10 μ g/mL)) surrogates or live rhinovirus (RV) 16 (MOI1). Cell-free supernatant was collected after 1 h for neutrophil elastase (NE) and matrix metalloproteinase- (MMP-) 9 measurements or after 24 h for CXCL8 release. Results . Constitutive NE was enhanced in A G o o d neutrophils compared to HC. fMLF stimulated neutrophils from A S u b o p t but not A G o o d produced 50% of HC levels. fMLF induced MMP-9 was impaired in A S u b o p t and A G o o d compared to HC. fMLF stimulated CXCL8 but not MMP-9 was positively correlated with FEV 1 and FEV 1 /FVC. A S u b o p t and A G o o d responded similarly to other stimuli. Conclusions . Circulating neutrophils are different in asthma however, this is likely to be related to airflow limitation rather than asthma control.
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.
Publisher: European Respiratory Society (ERS)
Date: 04-2021
Publisher: American Thoracic Society
Date: 05-2019
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.PUPT.2008.12.007
Abstract: Asthma is characterized by structural changes in the airways - airway remodelling. These changes include an increase in the bulk of the airway smooth muscle (ASM) and alterations in the profile of extracellular matrix (ECM) proteins in the airway wall. The mechanisms leading to airway remodelling are not well understood. ASM cells have the potential to play a key role in these processes through the production and release of ECM proteins. The ASM cells and ECM proteins are each able to influence the behaviour and characteristics of the other. The modified ECM profile in the asthmatic airway may contribute to the altered behaviour of the ASM cells, such responses to ECM proteins are modulated through the cell surface expression of integrin receptors. ASM cells from asthmatic in iduals express different levels of some integrin subunits compared to nonasthmatic ASM cells, which have the potential to further influence their responses to the ECM proteins in the airways. ECM homeostasis requires the presence and activation of matrix metalloproteinases and their tissue inhibitors, which in turn modulate the interaction of the ASM cells and the ECM proteins. Furthermore, the complex interactions of the ASM cells and the ECM in the asthmatic airways and the role played by external stimuli, such as viral infections, to modulate airway remodelling are currently unknown. This review summarises our current understanding of the influence of the ECM on ASM function.
Publisher: Wiley
Date: 09-2009
DOI: 10.1002/JMV.21556
Abstract: There is a lack of quantitative information about the generation of virus aerosols by infected subjects. The exhaled aerosols generated by coughing, talking, and breathing were s led in 50 subjects using a novel mask, and analyzed using PCR for nine respiratory viruses. The exhaled s les from a subset of 10 subjects who were PCR positive for rhinovirus were also examined by cell culture for this virus. Of the 50 subjects, among the 33 with symptoms of upper respiratory tract infections, 21 had at least one virus detected by PCR, while amongst the 17 asymptomatic subjects, 4 had a virus detected by PCR. Overall, rhinovirus was detected in 19 subjects, influenza in 4 subjects, parainfluenza in 2 subjects, and human metapneumovirus in 1 subject. Two subjects were co-infected. Of the 25 subjects who had virus-positive nasal mucus, the same virus type was detected in 12 breathing s les, 8 talking s les, and in 2 coughing s les. In the subset of exhaled s les from 10 subjects examined by culture, infective rhinovirus was detected in 2. These data provide further evidence that breathing may be a source of respirable particles carrying infectious virus.
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: Public Library of Science (PLoS)
Date: 13-10-2010
Publisher: Elsevier
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 16-01-2018
DOI: 10.1038/S41598-017-18429-0
Abstract: Asthma is an obstructive respiratory disease characterised by chronic inflammation with airway hyperresponsiveness. In asthmatic airways, there is an increase in airway smooth muscle (ASM) cell bulk, which differs from non-asthmatic ASM in characteristics. This study aimed to assess the usefulness of hTERT immortalisation of human ASM cells as a research tool. Specifically we compared proliferative capacity, inflammatory mediator release and extracellular matrix (ECM) production in hTERT immortalised and parent primary ASM cells from asthmatic and non-asthmatic donors. Our studies revealed no significant differences in proliferation, IL-6 and eotaxin-1 production, or CTGF synthesis between donor-matched parent and hTERT immortalised ASM cell lines. However, deposition of ECM proteins fibronectin and fibulin-1 was significantly lower in immortalised ASM cells compared to corresponding primary cells. Notably, previously reported differences in proliferation and inflammatory mediator release between asthmatic and non-asthmatic ASM cells were retained, but excessive ECM protein deposition in asthmatic ASM cells was lost in hTERT ASM cells. This study shows that hTERT immortalised ASM cells mirror primary ASM cells in proliferation and inflammatory profile characteristics. Moreover, we demonstrate both strengths and weaknesses of this immortalised cell model as a representation of primary ASM cells for future asthma pathophysiological research.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.HEALUN.2018.06.002
Abstract: Lung transplantation provides a unique opportunity to investigate the dynamics of the human pulmonary virome that is transplanted within the donor lungs. The pulmonary virome comprises both "resident" and "transient" viruses. In this study we aimed to analyze the dynamics of the "transient" members. We conducted a single-center, prospective, longitudinal investigation of community-acquired respiratory viruses detected in nasopharyngeal swabs, swabs of explanted and donor lungs, and serial bronchoalveolar lavages post-transplant. Fifty-two consecutive lung transplant recipients were recruited (bilateral:heart‒lung:bilateral lung-liver = 48:2:2) (age [mean ± SD] 48 ± 15 years, range 20 to 63 years 27 males and 25 females). Follow-up was 344 ± 120 (range 186 to 534) days. Seventeen of 45 explanted lungs were positive for influenza A and/or B (A = 14, B = 2, A+B = 1), despite recipient vaccination and negative nasal swabs, and 4 of 45 had human rhinovirus and 2 of 45 parainfluenza. Donor swabs showed influenza (A = 1, B = 1) and rhinovirus (n = 3). Day 1 lavage showed influenza A (n = 28), rhinovirus (n = 9), and parainfluenza (n = 1). Forty-seven of 52 recipients had a positive lavage for virus (38 of 47 on multiple lavages). Influenza persisted for 59 ± 38 (range 4 to 147) days in 27 of 52, and 14 had a single isolate. Rhinovirus persisted for 95 ± 84 (range 22 to 174) days in 13 of 52, and 13 had a single isolate. Analysis of 118 paired transbronchial biopsies and lavage demonstrated no association between viruses and acute cellular rejection (Fisher's exact test, 2 tailed, p = 1.00). Using a sensitive uniplex polymerase chain reaction we found that the transplanted pulmonary virome often includes community-acquired respiratory viruses, including influenza, which are variably persistent but not associated with acute rejection.
Publisher: The American Association of Immunologists
Date: 05-2013
DOI: 10.4049/JIMMUNOL.190.SUPP.136.3
Abstract: Cigarette smoke-induced chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory disorder of the lung. The development of effective therapies for COPD has been h ered by the lack of an animal model that mimics the human disease in a short time-frame.We have created a mouse model of cigarette smoke-induced COPD that develops the hallmark features of the human condition in a short amount of time. Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the development of the pathological features of COPD were assessed. The roles of macrophages and mast cell (MC) tryptase in pathogenesis were evaluated using depletion and in vitro studies and MC protease-6 deficient mice. After 8 weeks of smoke exposure, wild-type mice developed chronic inflammation, mucus hypersecretion, airway remodeling, emphysema, and reduced lung function. These characteristic features of COPD were glucocorticoid-resistant and did not spontaneously resolve. Systemic effects on skeletal muscle and the heart, and increased susceptibility to respiratory infections also were observed. We demonstrate here that macrophages and tryptase-expressing MCs were required for the development of COPD. Recombinant MC tryptase induced pro-inflammatory responses from cultured macrophages. This model can be used to better understand multiple aspects of COPD pathogenesis.
Publisher: American Thoracic Society
Date: 05-2020
DOI: 10.1164/AJRCCM-CONFERENCE.2020.201.1_MEETINGABSTRACTS.A4436
Publisher: Wiley
Date: 30-03-2020
DOI: 10.1002/PATH.5401
Publisher: MDPI AG
Date: 13-12-2022
DOI: 10.3390/PHARMACEUTICS14122788
Abstract: A primary illness that accounts for a significant portion of fatalities worldwide is cancer. Among the main malignancies, lung cancer is recognised as the most chronic kind of cancer around the globe. Radiation treatment, surgery, and chemotherapy are some medical procedures used in the traditional care of lung cancer. However, these methods lack selectivity and damage nearby healthy cells. Several polysaccharide-based nanomaterials have been created to transport chemotherapeutics to reduce harmful and adverse side effects and improve response during anti-tumour reactions. To address these drawbacks, a class of naturally occurring polymers called polysaccharides have special physical, chemical, and biological characteristics. They can interact with the immune system to induce a better immunological response. Furthermore, because of the flexibility of their structures, it is possible to create multifunctional nanocomposites with excellent stability and bioavailability for the delivery of medicines to tumour tissues. This study seeks to present new views on the use of polysaccharide-based chemotherapeutics and to highlight current developments in polysaccharide-based nanomedicines for lung cancer.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2016
DOI: 10.1038/SREP25881
Abstract: Maternal cigarette smoke exposure (SE) during gestation can cause lifelong adverse effects in the offspring’s brain. Several factors may contribute including inflammation, oxidative stress and hypoxia, whose changes in the developing brain are unknown. Female Balb/c mice were exposed to cigarette smoke prior to mating, during gestation and lactation. Male offspring were studied at postnatal day (P) 1, P20 and 13 weeks (W13). SE dams had reduced inflammatory mediators (IL-1β, IL-6 and toll like receptor (TLR)4 mRNA), antioxidant (manganese superoxide dismutase (MnSOD)) and increased mitochondrial activities (OXPHOS-I, III and V) and protein damage marker nitrotyrosine. Brain hypoxia-inducible factor (HIF)1α and its upstream signalling molecule early growth response factor (EGR)1 were not changed in the SE dams. In the SE offspring, brain IL-1R, IL-6 and TLR4 mRNA were increased at W13. The translocase of outer mitochondrial membrane and MnSOD were reduced at W13 with higher nitrotyrosine staining. HIF-1α was also increased at W13, although EGR1 was only reduced at P1. In conclusion, maternal SE increased markers of hypoxia and oxidative stress with mitochondrial dysfunction and cell damage in both dams and offspring and upregulated inflammatory markers in offspring, which may render SE dams and their offspring vulnerable to additional brain insults.
Publisher: Elsevier
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 03-05-2006
Publisher: MDPI AG
Date: 04-09-2023
Publisher: MDPI AG
Date: 06-04-2023
DOI: 10.3390/NU15071783
Abstract: Background: The gut microbiome, which can be altered by different diets or smoking, has been implicated in the pathogenesis of lung conditions. E-cigarette vaping is now recognised to have detrimental health effects, with several of these being similar to cigarette smoking. However, whether e-cigarettes can alter high-fat diet (HFD)-induced systemic effects and gut microbiota is unknown. In this study, we investigated the effects of HFD in the absence resence of e-cigarette exposure on systemic inflammation, lipid metabolic markers, and the gut microbiome. Methods: Mice were fed a HFD (or chow) in the absence resence of e-vapour exposure (±nicotine) and serum inflammation, lipid levels, and microbial ersity were assessed. Results: HFD increased the circulating levels of both triglycerides and non-esterified fatty acids, which were significantly reduced by e-vapour exposure in HFD-fed mice. Serum TNF-α was increased by HFD consumption or e-vapour. HFD had a significant effect on microbial ersity, but there were no additional effects of e-vapour exposure. Conclusions: This study highlights both similarities and differences in how the body responds to e-cigarette vapours, and it is therefore likely that the long-term sequelae of e-cigarette vapour exposure/vaping might not involve the significant alteration of the gut microbiome.
Publisher: Elsevier BV
Date: 08-2022
Publisher: American Physiological Society
Date: 06-2018
DOI: 10.1152/AJPLUNG.00438.2017
Abstract: Obesity is an important risk factor for developing severe asthma. Dietary fatty acids, which are increased in sera of obese in iduals and after high-fat meals, activate the innate immune system and induce inflammation. This study investigated whether dietary fatty acids directly cause inflammation and/or synergize with obesity-induced cytokines in primary human pulmonary fibroblasts in vitro. Fibroblasts were challenged with BSA-conjugated fatty acids [ω-6 polyunsaturated fatty acids (PUFAs) and ω-3 PUFAs or saturated fatty acids (SFAs)], with or without TNF-α, and release of the proinflammatory cytokines, IL-6 and CXCL8, was measured. We found that the ω-6 PUFA arachidonic acid (AA), but not ω-3 PUFAs or SFAs, upregulates IL-6 and CXCL8 release. Combined AA and TNF-α challenge resulted in substantially greater cytokine release than either alone, demonstrating synergy. Synergistic upregulation of IL-6, but not CXCL8, was mainly mediated via cyclooxygenase (COX). Inhibition of p38 MAPK reduced CXCL8 release, induced by AA and TNF-α alone, but not in combination. Synergistic CXCL8 release, following AA and TNF-α challenge, was not medicated via a single signaling pathway (MEK1, JNK, phosphoinositide 3-kinase, and NF-κB) nor by hyperactivation of NF-κB or p38. To investigate if these findings occur in other airway cells, effects of AA in primary human airway smooth muscle (ASM) cells and human bronchial epithelial cells were also investigated. We found proinflammatory effects in ASM cells but not epithelial cells. This study suggests that diets rich in ω-6 PUFAs might promote airway inflammation via multiple pathways, including COX-dependent and -independent pathways, and in an obese person, may lead to more severe airway inflammation.
Publisher: MDPI AG
Date: 25-08-2016
DOI: 10.3390/IJMS17091403
Publisher: Public Library of Science (PLoS)
Date: 23-01-2014
Publisher: BMJ
Date: 10-2007
Publisher: Wiley
Date: 15-10-2019
Abstract: Maternal first- or second-hand tobacco smoking during pregnancy is still common albeit that the detrimental effects to the unborn child are well known. Maternal tobacco cigarette smoking can affect multiple organ systems in the offspring, rendering them at increased risk of various conditions throughout life (eg. intrauterine underdevelopment, asthma, substance abuse, diabetes). However, this review will only focus on its impact on the brain and the related molecular changes in the offspring based on evidence from animal studies. Although epidemiological studies have identified the associations between maternal cigarette smoke exposure (SE) and brain disorders, animal models can help identify the underlying mechanisms and test interventions. Human studies have found that maternal SE is closely linked to small brain size and changes in brain structure and associated with a high risk of cognitive defects. Animal models suggest that this may be due to increased brain oxidative stress and inflammation during the neonatal period, leading to increased brain cell apoptosis in adulthood. There is a distinct gender bias of such impacts, where male offspring are more affected than females. Female offspring seem to have developed the adaptation by increasing endogenous antioxidant levels. Indeed, animal studies have shown that using antioxidant supplementation during pregnancy can improve neurological outcomes in male offspring, however, the efficacy in humans is yet to be confirmed. Furthermore, some animal studies suggested nicotine as the key player in intrauterine underdevelopment due to maternal SE, while human clinical trials using nicotine replacement therapy do not support this mechanism. This review will discuss the possible reasons.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Wiley
Date: 08-09-2016
DOI: 10.1002/JMV.24371
Abstract: Much of what is known about the seasonality of human rhinovirus (hRV) infections has been learned from the study of acute asthma exacerbations presenting to emergency care, including those among children at the start of the school term. Much less is known about the patterns of hRVs in the community. In this study, viruses and day-to-day symptoms of asthma and colds were monitored twice weekly in 67 children with asthma aged 5-12 years, over a 15 month period in Sydney, Australia. Overall hRV was detected in 314/1232 (25.5%) of nasal wash s les and 142/1231 (11.5%) of exhaled breath s les of these, 231 and 24 respectively were genotyped. HRVs were detected with similar prevalence rate throughout the year, including no peak in hRV prevalence following return to school. No peaks were seen in asthma and cold symptoms using twice-weekly diary records. However, over the same period in the community, there were peaks in asthma emergency visits both at a large local hospital and in state-wide hospitalizations, following both return to school (February) and in late autumn (May) in children of the same age. This study suggests that hRV infections are common throughout the year among children, and differences in virus prevalence alone may not account for peaks in asthma symptoms.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Hindawi Limited
Date: 02-07-2202
DOI: 10.1155/2021/9892088
Abstract: Objective. Cinnamon is a cooking spice and a medicinal herb. It is increasingly used as a health supplement due to its perceived benefit to prevent and or manage type 2 diabetes and metabolic disorders. However, it is unclear if regular consumption of this medicinal plant will interfere with normal physiological functions. Therefore, this study investigated the impact of daily cinnamon supplements on glucose and lipid metabolic profiles in healthy rats. Methods. Male rats (Sprague Dawley, 8 weeks) were supplied with cinnamon in their diet (equivalent to ∼1 g/day in humans) for two weeks. Blood glucose and lipid levels, as well as metabolic markers in both liver and abdominal white adipose tissue, were measured. Results. Cinnamon significantly increased fat mass and blood cholesterol and low-density lipoprotein (LDL) levels, but reduced fasting blood glucose level by 12%. Liver functional enzymes were normal in rats consuming cinnamon. However, several lipid metabolic markers were impaired which may contribute to dyslipidemia, including two main switches for energy metabolism (sirtuin 1 and peroxisome proliferator-activated receptor-gamma coactivator-1α) and the LDL receptor. However, de novo lipid synthesis enzymes and inflammatory markers were also reduced in the liver by cinnamon treatment, which may potentially prevent the development of steatosis. Markers for lipid oxidation were downregulated in fat tissue in cinnamon-treated rats, contributing to increased fat accumulation. Conclusion. Daily low-dose cinnamon supplementation seems to promote abdominal adipose tissue accumulation and disturb lipid homeostasis in healthy rats, raising the concerns regarding daily use in healthy people.
Publisher: Public Library of Science (PLoS)
Date: 15-02-2013
Publisher: Wiley
Date: 06-2009
DOI: 10.1111/J.1398-9995.2009.01959.X
Abstract: CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on ASM CD40 and OX40L expression. CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-alpha and/or IFN-gamma was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. Interferon-gamma and TNF-alpha synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-gamma reduced TNF-alpha-induced OX40L expression to a similar extent in both cell types. TNF-alpha and IFN-gamma induced CD40 via nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-kappaB and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-kappaB, but these were not statistically significant. The reduced OX40L expression with TNF-alpha and IFN-gamma involved extracellular regulated kinase 1/2 activation. Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-gamma may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression.
Publisher: MDPI AG
Date: 28-03-2023
DOI: 10.3390/IJMS24076378
Abstract: Cardiovascular disease (CVD) is a leading cause of mortality worldwide, with cigarette smoking being a major preventable risk factor. Smoking cessation can be difficult due to the addictive nature of nicotine and the withdrawal symptoms following cessation. Electronic cigarettes (e-Cigs) have emerged as an alternative smoking cessation device, which has been increasingly used by non-smokers however, the cardiovascular effects surrounding the use of e-Cigs remains unclear. This study aimed to investigate the effects of e-Cig aerosol condensate (EAC) (0 mg and 18 mg nicotine) in vitro on human coronary artery endothelial cells (HCAEC) and in vivo on the cardiovascular system using a mouse model of ‘e-vaping’. In vitro results show a decrease in cell viability of HCAEC when exposed to EAC either directly or after exposure to conditioned lung cell media (p 0.05 vs. control). Reactive oxygen species were increased in HCAEC when exposed to EAC directly or after exposure to conditioned lung cell media (p 0.0001 vs. control). ICAM-1 protein expression levels were increased after exposure to conditioned lung cell media (18 mg vs. control, p 0.01). Ex vivo results show an increase in the mRNA levels of anti-angiogenic marker, FKBPL (p 0.05 vs. sham), and endothelial cell adhesion molecule involved in barrier function, ICAM-1 (p 0.05 vs. sham) in murine hearts following exposure to electronic cigarette aerosol treatment containing a higher amount of nicotine. Immunohistochemistry also revealed an upregulation of FKBPL and ICAM-1 protein expression levels. This study showed that despite e-Cigs being widely used for tobacco smoking cessation, these can negatively impact endothelial cell health with a potential to lead to the development of cardiovascular disease.
Publisher: Wiley
Date: 20-10-2016
Abstract: Traumatic brain injury (TBI) remains one of the leading causes of death and disability worldwide. Mild TBI may lead to neuropsychiatric sequelae, including memory loss and motor impairment. Mitochondrial dysfunction and oxidative stress have a contributory role in several neurological disorders however, their association with mitophagy in mild TBI is unclear. TBI was induced in female Sprague Dawley (SD) rats using a New York University Impactor (10 g, impactor head 2.5 mm diameter, weight drop 50 mm) and compared to sham surgery controls. The novel object recognition and error ladder tests were performed at 24 hours and for 6 weeks post injury, and the brains were examined histologically to confirm the extent of injury. Mitochondria manganese superoxide dismutase (MnSOD) and the oxidative phosphorylation (OXPHOS) complexes I-V (CI-CV), as well as mitophagy markers, dynamin related protein 1 (DRP-1), LC3A/B and PTEN-induced putative kinase 1 (PINK-1), were measured in the penumbra by western blot. At 24 hours sham rats performed as expected on a novel object recognition test while TBI rats showed cognitive deficits at the early time points. TBI rats also showed more early motor deficits on a horizontal ladder, compared with the sham rats. MnSOD, OXPHOS CI, CIII and CV protein levels were significantly lower in the TBI group at 24 hours. DRP-1, LC3A/B I and II, and PINK-1 were increased at 6 weeks suggesting abnormal mitophagy. Moderate TBI caused immediate cognitive and mild motor functional deficits in the rats that did not persist. Reduced antioxidative capacity and possibly compromised mitochondrial function may affect the long term functional recovery.
Publisher: Hindawi Limited
Date: 05-10-2021
DOI: 10.1111/JFBC.13954
Abstract: Metastasis represents the leading cause of death in lung cancer patients. C-X-C Motif Chemokine Ligand 8 (CXCL-8), Chemokine (C-C motif) ligand 20 (CCL-20) and heme oxygenase -1 (HO-1) play an important role in cancer cell proliferation and migration. Berberine is an isoquinoline alkaloid isolated from several herbs in the Papaveraceae family that exhibits anti-inflammatory, anticancer and antidiabetic properties. Therefore, the aim of present study is to investigate the inhibitory potential of berberine monoolein loaded liquid crystalline nanoparticles (berberine-LCNs) against cancer progression. Berberine-LCNs were prepared by mixing berberine, monoolein and poloxamer 407 (P407) using ultrasonication method. A549 cells were treated with or without 5 µM dose of berberine LCNs for 24 hr and total cellular protein was extracted and further analyzed for the protein expression of CCl-20, CXCL-8 and HO-1 using human oncology array kit. Our results showed that berberine-LCNs significantly reduced the expression of CCl-20, CXCL-8 and HO-1 at dose of 5µM. Collectively, our findings suggest that berberine-LCNs have inhibitory effect on inflammation/oxidative stress related cytokines i.e. CCL20, CXCL-8, and HO-1 which could be a novel therapeutic target for the management of lung cancer. PRACTICAL APPLICATIONS: Berberine is an isoquinoline alkaloid extracted from various plants of Papaveraceae family. CXCL-8, CCL-20 and HO-1 play an important role in cancer progression. Our study showed that Berberine LCNs significantly downregulate the expression of CXCL-8, CCL-20 and HO-1 which suggests that Berberine loaded nanoparticles could be a promising therapeutic alternative for the management of lung cancer.
Publisher: Elsevier BV
Date: 03-2015
Publisher: The American Association of Immunologists
Date: 05-2018
DOI: 10.4049/JIMMUNOL.200.SUPP.180.30
Abstract: Malaria is one of the oldest and deadliest diseases known to humans, and in 2017 an estimated 216 million people were infected with 445,000 succumbing to disease. Antibodies which block the skin-to-liver stages of malaria infection continue to be pursued due to their potential to stop infection prior to the progression to the disease and transmission-causing blood stages. Phase III clinical trials with a vaccine targeting the major sporozoite surface protein (circumsporozoite protein) have provided suboptimal efficacy in the field which must be improved before large scale use for malaria prevention and eradication. New antibody targets will likely be needed in order to provide complete, sterilizing protection. Thus far, the search has largely been limited to targeting surface and secreted proteins of the sporozoite, merozoite or gametocyte stages. Here, we present data demonstrating that antibodies which instead target the intracellular liver stage parasite after hepatocyte infection can be a potent means of limiting parasite liver infection in vivo. This was done in a rodent malaria model by targeting two different proteins found on the parasitophorous vacuole membrane that forms the border between parasite and host cytoplasm—indicating antibodies are entering the hepatocyte to mediate their effect. This phenomenon was also demonstrated using the most common human malaria species Plasmodium falciparum in humanized liver chimeric mice where human antibodies targeting the parasite periphery were able to potently reduce liver burden and parasite liver growth between days 5–6. These data present a new class of antibody targets for malaria and strongly argue for the inclusion of intracellular antigens in novel vaccine formulations.
Publisher: Wiley
Date: 21-11-2016
Abstract: Increased oxidative stress in the brain can lead to increased sympathetic tone that may further induce kidney dysfunction. Previously we have shown that maternal cigarette smoke exposure (SE) leads to significantly increased oxidative stress and inflammation in both brain and kidney, as well as reduced brain and kidney mitochondrial activity. This is closely associated with significant kidney underdevelopment and abnormal function in adulthood in the male offspring. This study aimed to investigate the impact of maternal SE on brain and kidney health in the female offspring. In this study, the mouse dams were exposed to two cigarettes, twice daily for 6 weeks prior to gestation, during pregnancy and lactation. Brains and kidneys from the female offspring were collected at 20 days (P20) and 13 weeks (W13) and were subject to further analysis. We found that mRNA expression of brain inflammatory markers interleukin-1 receptor and Toll-like receptor 4 were significantly increased in the SE offspring at both P20 and W13. Their brain mitochondrial activity markers were however increased at W13 with increased antioxidant activity. Kidney development and function in the female SE offspring were not different from the control offspring. We concluded that although brain inflammatory markers were upregulated in the SE female offspring, they were protected from some of the indicators of brain oxidative stress, such as endogenous antioxidant and mitochondrial dysfunction, as well as abnormal kidney development and function in adulthood.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.COPBIO.2021.10.025
Abstract: Elastic fibers are an essential part of the pulmonary extracellular matrix (ECM). Intact elastin is required for normal function and its damage contributes profoundly to the etiology and pathology of lung disease. This highlights the need for novel lung-specific imaging methodology that enables high-resolution 3D visualization of the ECM. We consider elastin's involvement in chronic respiratory disease and examine recent methods for imaging and modeling of the lung in the context of advances in lung tissue engineering for research and clinical application.
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.
Publisher: Wiley
Date: 12-12-2016
DOI: 10.1111/AJI.12450
Abstract: Successful implantation requires synchronous development of embryo and endometrium. Endometrial receptivity results from progesterone-induced differentiation of endometrial cells, generally achieved during the mid-secretory phase of the cycle. Failure to properly develop receptivity results in failed or inadequate implantation and hence no ongoing pregnancy. The blastocyst undergoes final development, apposition, attachment and initiates invasion of the endometrial epithelium within the uterine cavity. Thus, the microenvironment provided by uterine fluid, particularly glandular secretions, is essential for implantation. Analysis of endometrial fluid has identified cytokines, chemokines, proteases, antiproteases and other factors that modulate blastocyst functions relevant to implantation. Exosomes/microvesicular bodies released from the endometrium (and likely also the embryo) are present in uterine fluid. These can transfer miRNA, proteins and lipids between cells, thus providing endometrial-embryo communication in the peri-implantation period. Understanding the uterine microenvironment, and its effects on endometrial-embryo interactions, will provide opportunities to modify current infertility treatments to improve success rates.
Publisher: Wiley
Date: 17-07-2019
DOI: 10.1111/NYAS.14174
Abstract: Maternal smoking during pregnancy is a significant risk factor of renal pathology in the offspring. E-cigarettes are perceived to be a safe option and are increasingly used by pregnant women either continuously during pregnancy or as a replacement for tobacco cigarettes. This study aimed to determine the effects of replacing tobacco cigarettes with e-cigarettes during pregnancy, and continuous e-cigarette use during pregnancy on the offspring's kidneys. Female Balb/c mice were exposed to either air (sham) or tobacco cigarette smoke (SE) for 6 weeks prior to mating, during gestation and lactation. A subset of the "SE group" received e-cigarette vapor (containing nicotine) after mating until pups weaned. Additional female mice were continuously exposed to e-vapor (either with or without nicotine) for 6 weeks prior to mating until pups weaned. Kidneys and urine from the male offspring were assessed at postnatal day 1, day 20 (weaning), and 13 weeks of age (adulthood). E-cigarette replacement was less detrimental to renal development and albuminuria than continuous SE during pregnancy. However, continuous e-vapor exposure during pregnancy increased markers of oxidative stress, inflammation, and fibrosis in the adult offspring, independent of nicotine. E-cigarette use during pregnancy confers future risk to the offspring's kidneys.
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.
Start Date: 2013
End Date: 2016
Funder: Australian Research Council
View Funded ActivityStart Date: 2010
End Date: 2012
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 06-2023
Amount: $335,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 04-2014
End Date: 04-2017
Amount: $370,000.00
Funder: Australian Research Council
View Funded Activity