ORCID Profile
0000-0001-5676-6126
Current Organisations
The University of Newcastle
,
Alfred Health
,
Monash University
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Publisher: Wiley
Date: 06-02-2020
DOI: 10.1111/RESP.13774
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Future Medicine Ltd
Date: 12-2020
Abstract: Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent various physicochemical characterization experiments, an in vitro release study, molecular simulations and was evaluated for in vitro anti-inflammatory activity. Results: Results showed that Nio-Curc had a mean particle size of 284.93 ± 14.27 nm, zeta potential of -46.93 and encapsulation efficacy of 99.62%, which demonstrates optimized physicochemical characteristics. Curcumin release in vitro could be sustained for up to 24 h. Additionally, Nio-Curc effectively reduced mRNA transcript expression of pro-inflammatory markers IL-6, IL-8, IL-1β and TNF-α in immortalized human airway basal cell line (BCi-NS1.1). Conclusion: In this study, we have demonstrated that Nio-Curc mitigated the mRNA expression of pro-inflammatory markers in an in vitro study, which could be applied to treatment of asthma with further studies.
Publisher: European Respiratory Society
Date: 15-09-2018
Publisher: European Respiratory Society (ERS)
Date: 2002
DOI: 10.1183/09031936.02.00226302
Abstract: Acute exacerbations of asthma are frequently caused by viral infections, but the inflammatory mechanisms in virus-induced asthma are poorly understood. The aim of the present study was to determine whether viral infection in acute asthma was associated with increased sputum neutrophil degranulation and increased cellular lysis and whether these changes are related to clinical severity. Adults (n=49) presenting to the emergency department with acute asthma were examined for infection by means of sputum direct-fluorescence antigen detection, sputum culture, and sputum polymerase chain reaction for Mycoplasma, Chlamydia and Legionella pneumophila, and all common respiratory viruses. Subjects infected with one of these agents were classed as having an infective exacerbation. Spirometry and sputum induction were performed on presentation and 4-5 weeks later. Thirty-seven subjects (76%) had virus infection and acute asthma. Those with virus infection had increased sputum neutrophils (p<0.05) and increased neutrophil elastase (p<0.05), this was related to increased elevated sputum lactate dehydrogenase (LDH). Subjects with noninfective asthma had an increase in the proportion of sputum eosinophils. Both groups had elevated sputum eosinophil cationic protein (ECP) concentrations. Higher levels of sputum LDH and ECP were associated with a longer hospital stay. Virus infection and acute asthma is associated with neutrophilic inflammation, cell lysis and more severe clinical disease.
Publisher: Wiley
Date: 28-04-2023
DOI: 10.1111/RESP.14506
Abstract: Type 2 (T2) innate lymphoid cells (ILC2s) contribute to airway inflammation and disease in asthma. We hypothesize that ILC2s isolated from people with severe allergic and eosinophilic asthma would exhibit an enhanced T2 inflammatory activity that would be altered following treatment with mepolizumab and omalizumab. We compare peripheral blood (PB) isolated ILC2's proliferative capacity, IL‐5 and IL‐13 secretion and phenotype between healthy without asthma (HC), non‐asthma allergic (NAA), mild asthma (MA) and severe allergic and eosinophilic asthma (SA) subjects. We then determined the impact of 6 months treatment with either mepolizumab or omalizumab on ILC2s physiology of SA subjects. ILC2s were sorted and cultured in the presence of IL‐2, IL‐25, IL‐33 and thymic stromal lymphopoietin (TSLP) for 14 days. ILC2s proliferation, phenotypes and functions were assessed using flowcytometry. The ILC2s response was then reassessed following clinically successful treatment of SA subjects with mepolizumab and omalizumab. SA ILC2s demonstrated increased proliferative capacity, TSLP receptor (TSLPR), GATA3 and NFATc1 protein expressions and increased IL‐5 and IL‐13 release. ILC2s were also capable of releasing IL‐6 in response to stimulation. Mepolizumab treatment reduced ILC2s proliferative capacity and expression of TSLPR, GATA3 and NFATc1. Both mepolizumab and omalizumab were associated with reduced ILC2s release of IL‐5 and IL‐13, only mepolizumab reduced IL‐6. ILC2s from severe allergic and eosinophilic asthma demonstrated an active phenotype typified by increased proliferation, TSLPR, GATA3 and NFATc1 expression and increased IL‐5, IL‐13 and IL‐6 release. Mepolizumab reduced markers of ILC2s activation.
Publisher: SAGE Publications
Date: 05-07-2021
Publisher: BMJ
Date: 08-2011
Publisher: BMJ
Date: 2019
DOI: 10.1136/BMJOPEN-2018-024330
Abstract: The significance of neutrophilic inflammation in obstructive airway disease remains controversial. Recent studies have demonstrated presence of an active neutrophil population in systemic circulation, featuring hypersegmented morphology, with high oxidative burst and functional plasticity in inflammatory conditions. The aim of this study was to characterise neutrophil subsets in bronchial lavage (BL) of obstructive airway disease participants (asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis) and healthy controls on the basis of nuclear morphology and to assess the association between neutrophil subsets and the clinical parameters of the obstructive airway disease participants. A cross-sectional exploratory study. John Hunter Hospital and Hunter Medical Research Institute, Australia. Seventy-eight adults with obstructive airway disease comprised those with stable asthma (n=39), COPD (n=20) and bronchiectasis (n=19) and 20 healthy controls. Cytospins were prepared and neutrophil subsets were classified based on nuclear morphology into hypersegmented ( lobes), normal (2–4 lobes) and banded (1 lobe) neutrophils and enumerated. Neutrophils from each subset were identified in all participants. Numbers of hypersegmented neutrophils were elevated in participants with airway disease compared with healthy controls (p .001). Both the number and the proportion of hypersegmented neutrophils were highest in COPD participants (median (Q1–Q3) of 1073.6 (258.8–2742) × 10 2 /mL and 24.5 (14.0–46.5)%, respectively). An increased proportion of hypersegmented neutrophils in airway disease participants was significantly associated with lower forced expiratory volume in 1 s/forced vital capacity per cent (Spearman’s r=−0.322, p=0.004). Neutrophil heterogeneity is common in BL and is associated with more severe airflow obstruction in adults with airway disease. Further work is required to elucidate the functional consequences of hypersegmented neutrophils in the pathogenesis of disease.
Publisher: Mary Ann Liebert Inc
Date: 15-11-2010
Abstract: Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are a significant and increasing global health problem. These diseases are characterized by airway inflammation, which develops in response to various stimuli. In asthma, inflammation is driven by exposure to a variety of triggers, including allergens and viruses, which activate components of both the innate and acquired immune responses. In COPD, exposure to cigarette smoke is the primary stimulus of airway inflammation. Activation of airway inflammatory cells leads to the release of excessive quantities of reactive oxygen species (ROS), resulting in oxidative stress. Antioxidants provide protection against the damaging effects of oxidative stress and thus may be useful in the management of inflammatory airways disease. Resveratrol, a polyphenol that demonstrates both antioxidative and anti-inflammatory functions, has been shown to improve outcomes in a variety of diseases, in particular, in cancer. We review the evidence for a protective role of resveratrol in respiratory disease. Mechanisms of resveratrol action that may be relevant to respiratory disease are described. We conclude that resveratrol has potential as a therapeutic agent in respiratory disease, which should be further investigated.
Publisher: Massachusetts Medical Society
Date: 29-04-2019
Publisher: European Respiratory Society
Date: 15-09-2018
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Wiley
Date: 19-10-2012
Publisher: Elsevier BV
Date: 03-2008
Publisher: Oxford University Press (OUP)
Date: 03-2010
DOI: 10.1002/IBD.21097
Abstract: The two forms of human inflammatory bowel disease, Crohn's disease (CD) and ulcerative colitis (UC), are both associated with loss of tolerance to gut microbial antigens. The dominant antigen recognized by antibody and T-cell responses in patients with CD is bacterial flagellin. Flagellin is also the only known ligand for Toll-like receptor 5 (TLR5), a key protein in innate immunity. Although flagellin activates TLR5 to produce inflammatory responses in many cell types in the gut, there is conflicting evidence as to whether TLR5 is harmful or protective in CD and murine colitis models. A recent study found that administration of flagellin enemas to mice along with dextran sodium sulfate (DSS) made their colitis worse. We sought to determine whether this exacerbation was due to TLR5 ligation, or to TLR5-independent adaptive immune responses to flagellin as an antigen, by using a transposon insertional mutant of the Escherichia coli H18 flagellin, 2H3, which lacks TLR5 stimulatory activity. We found that flagellin enemas produced only a mild exacerbation of DSS colitis, and that 2H3 was equivalent to or worse than wildtype flagellin. Moreover, we found that DSS colitis was more severe in TLR5(-/-) mice than wildtype C57BL/6 mice. Together, these results suggest that flagellin-mediated exacerbation of colitis is independent of TLR5.
Publisher: American Society for Clinical Investigation
Date: 22-08-2019
Publisher: European Respiratory Society
Date: 04-09-2022
Publisher: European Respiratory Society (ERS)
Date: 08-2023
Publisher: European Respiratory Society (ERS)
Date: 05-12-2020
DOI: 10.1183/13993003.01509-2019
Abstract: Treatable traits have been proposed as a new paradigm for airway disease management. To characterise treatable traits in a severe asthma population and to determine the efficacy of targeting treatments to these treatable traits in severe asthma. Participants (n=140) with severe asthma were recruited to a cross-sectional study and underwent a multidimensional assessment to characterise treatable traits. Eligible participants with severe asthma (n=55) participated in a 16-week parallel-group randomised controlled trial to determine the feasibility and efficacy of management targeted to predefined treatable traits, compared to usual care in a severe asthma clinic. The patient-reported outcome of health-related quality of life was the trial's primary end-point. Participants with severe asthma had a mean± sd of 10.44±3.03 traits per person, comprising 3.01±1.54 pulmonary and 4.85±1.86 extrapulmonary traits and 2.58±1.31 behavioural/risk factors. In idualised treatment that targeted the traits was feasible and led to significantly improved health-related quality of life (0.86 units, p .001) and asthma control (0.73, p=0.01). Multidimensional assessment enables detection of treatable traits and identifies a significant trait burden in severe asthma. Targeting these treatable traits using a personalised-medicine approach in severe asthma leads to improvements in health-related quality of life, asthma control and reduced primary care acute visits. Treatable traits may be an effective way to address the complexity of severe asthma.
Publisher: American Thoracic Society
Date: 15-07-2020
Publisher: American Thoracic Society
Date: 03-2005
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Elsevier BV
Date: 11-2020
Publisher: Springer Science and Business Media LLC
Date: 14-10-2007
DOI: 10.1038/NM1660
Abstract: The role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (T(H)2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10(-/-)) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits T(H)2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10(-/-) mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Elsevier BV
Date: 2017
Publisher: Wiley
Date: 23-11-2011
DOI: 10.1111/J.1365-2222.2011.03892.X
Abstract: In 2010 over 200 articles were published in Clinical and Experimental Allergy including editorials, reviews, opinion articles, letters, book reviews and of course at the heart of the journal, papers containing original data which have moved the field of allergy forward on a number of fronts. For the third year running the editors felt it would be of value to summarize the key messages contained in these papers as a snapshot of where the cutting edge of research into allergic disease is leading. We have broadly followed the sections of the journal, although this year the mechanistic articles are grouped together and the studies involving experimental models of disease are discussed throughout the paper. In the field of asthma and rhinitis phenotypes and biomarkers continue to a major pre-occupation of our authors. There is continued interest in mechanisms of inflammation and disordered lung function with the mouse model of asthma continuing to offer new insights. There is also a steady flow of papers investigating new therapies, including those derived from plants and herbs, although many are mechanistic with too few high quality clinical trials. The mechanisms involved in allergic disease are well covered with many strong papers using clinical material to ask relevant questions. Pro-pre and snybiotics continue to be of major interest to our authors and this remains a controversial and complicated field. The discipline of epidemiology has retained its interest in risk factors for the development of allergic disease with a view to refining and debating the reasons for the allergy epidemic. There is continued interest in the relationship between helminthic disease and allergy with a new twist in 2010 involving studies using infection with helminths as a potential treatment. The genetics of allergic disease continues to be very productive, although the field has moved on from only investigating single nucleotide polymorphisms of candidate genes to Genome Wide Association Studies and an increasing and welcome emphasis on gene-environment interactions. In the field of clinical allergy there is steady flow of papers describing patterns of drug allergy with renewed interest in reactions to contrast media, but food allergy is the major area of interest in this section of the journal. Lastly in the field of allergens there is a growing interest in the role of component resolved diagnosis in improving the diagnosis and management of allergic disease. Another excellent year, full of fascinating and high quality work, which the journal has been proud to bring to the allergy community.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2013
DOI: 10.1007/S00296-013-2771-7
Abstract: Bisphosphonates such as alendronate, risedronate and zoledronate have revolutionised the treatment for osteoporosis and Paget's disease. These drugs reduce fracture risk and probably mortality in patients with osteoporosis. However, they have a long in vivo half-life following cessation and may be associated with delayed dental healing and even the devastating complication of osteonecrosis of the jaw (ONJ). Extensive media attention highlighting this issue has caused much concern among patients and healthcare professionals. This paper seeks to provide treating clinicians with a balanced multi-disciplinary review of the available evidence pertaining to this issue and practical advice regarding prevention and management of ONJ.
Publisher: European Respiratory Society (ERS)
Date: 10-2021
DOI: 10.1183/23120541.00448-2020
Abstract: Patient-oriented research approaches that reflect the needs and priorities of those most affected by health research outcomes improves translation of research findings into practice. Targeted therapies for cystic fibrosis (CF) are now a viable treatment option for some eligible in iduals despite the heterogeneous patient-specific therapeutic response. This has necessitated development of a clinical tool that predicts treatment response for in idual patients. Patient-derived mini-organs (organoids) have been at the forefront of this development. However, little is known about their acceptability in CF patients and members of the public. We used a cross-sectional observational design to conduct an online survey in people with CF, their carers and community comparisons. Acceptability was examined in five domains: 1) willingness to use organoids, 2) perceived advantages and disadvantages of organoids, 3) acceptable out-of-pocket costs, 4) turnaround time and 5) source of tissue. In total, 188 participants completed the questionnaire, including adults with CF and parents of children with CF (90 (48%)), and adults without CF and parents of children without CF (98 (52%)). Use of organoids to guide treatment decisions in CF was acceptable to 86 (95%) CF participants and 98 (100%) community participants. The most important advantage was that organoids may improve treatment selection, improving the patient's quality of life and life expectancy. The most important disadvantage was that the organoid recommended treatment might be unavailable or too expensive. These findings indicate acceptance of patient-derived organoids as a tool to predict treatment response by the majority of people surveyed. This may indicate successful future implementation into healthcare systems.
Publisher: WORLD SCIENTIFIC
Date: 03-2011
Publisher: European Respiratory Society (ERS)
Date: 05-03-2020
DOI: 10.1183/13993003.02420-2019
Abstract: Severe asthma is a high-burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are applicable in a broader population. The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia. Patients (n=309) with severe eosinophilic asthma (median age 60 years, 58% female) commenced mepolizumab. They had poor symptom control (median Asthma Control Questionnaire (ACQ)-5 score of 3.4), frequent exacerbations (median three courses of oral corticosteroids (OCS) in the previous 12 months), and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590 cells·µL −1 . Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%. Mepolizumab treatment reduced exacerbations requiring OCS compared with the previous year (annualised rate ratio 0.34 (95% CI 0.29–0.41) p .001) and hospitalisations (rate ratio 0.46 (95% CI 0.33–0.63) p .001). Treatment improved symptom control (median ACQ-5 reduced by 2.0 at 6 months), quality of life and lung function. Higher blood eosinophil levels (p=0.003) and later age of asthma onset (p=0.028) predicted a better ACQ-5 response to mepolizumab, whilst being male (p=0.031) or having body mass index ≥30 (p=0.043) predicted a lesser response. Super-responders (upper 25% of ACQ-5 responders, n=61, 24%) had a higher T2 disease burden and fewer comorbidities at baseline. Mepolizumab therapy effectively reduces the significant and long-standing disease burden faced by patients with severe eosinophilic asthma in a real-world setting.
Publisher: Public Library of Science (PLoS)
Date: 16-07-2013
Publisher: American Thoracic Society
Date: 15-09-2021
Publisher: American Thoracic Society
Date: 15-02-2019
Publisher: American Physiological Society
Date: 08-2023
DOI: 10.1152/AJPLUNG.00074.2022
Abstract: Bronchoconstriction is the main physiological event in asthma, which leads to worsened clinical symptoms and generates mechanical stress within the airways. Virus infection is the primary cause of exacerbations in people with asthma, however, the impact of bronchoconstriction on host antiviral responses and viral replication is unknown. We developed two disease models, in vitro, and found suppressed IFN response from cells following the application of compression and RV-A1 infection. This explains why people with asthma have deficient IFN response.
Publisher: American College of Physicians
Date: 19-07-2011
Publisher: Wiley
Date: 04-03-2020
DOI: 10.1111/RESP.13794
Publisher: BMJ
Date: 10-2006
Publisher: European Respiratory Society (ERS)
Date: 10-12-2020
DOI: 10.1183/13993003.01584-2020
Abstract: We assessed whether Toll-like receptor (TLR)2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases. We employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III interferon (IFN) production, as well as the lung tissue and epithelial cell immune transcriptome. We show, in vivo , that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7 days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1 day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7 days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro , INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for nuclear factor (NF)-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response. Airway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Australian Government Department of Health
Date: 26-04-2022
Abstract: Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2019 influenza season. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Cases were defined as patients hospitalised at any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data were also collected on a frequency matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 1 April to 31 October 2019 (the 2019 influenza season), there were 4,154 patients admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 44% were elderly (≥ 65 years), 21% were children ( 16 years), 7.7% were Aboriginal and Torres Strait Islander peoples, 1.7% were pregnant and 73% had chronic comorbidities. Most admissions were due to influenza A infection (85%). Estimated vaccine coverage was 75% in the elderly, 49% in non-elderly adults with medical comorbidities, and 27% in young children ( 5 years). The estimated vaccine effectiveness in the target adult population was 42% (95% confidence interval [95% CI]: 36%, 49%). There were a larger number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2019 than in 2018.
Publisher: Future Science Ltd
Date: 04-2018
Abstract: Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Such systems use particles at a nanoscale range, bringing about their intended use through a range of complex mechanisms. Apart from delivering drug substances into target tissues, these vesicular systems also effectively overcome problems like insolubility and unequal drug distribution. Several mechanisms are explored lately by different workers, and interest over vesicular curcumin has been renewed in the past decade. This commentary discusses several immunological targets in which curcumin is employed in a vesicular form.
Publisher: Australian Government Department of Health
Date: 2022
Abstract: Introduction Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. Methods The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Influenza and COVID-19 cases were defined as patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. Results There were 448 patients with COVID-19 admitted between 16 March and 31 December 2020, and only 20 patients with influenza admitted between 1 April and 30 November 2020, to one of 22 FluCAN hospitals. Of the COVID-19 cases, 173 (39%) were 65 years of age, 36 (8%) were children ( 16 years), 6 (1%) were Aboriginal and Torres Strait Islander peoples, 4 (1%) were pregnant and 289 (65%) had chronic comorbidities. COVID-19 hospital admissions peaked between weeks 13 and 15 (first wave) nationally, and again between weeks 31 and 35 (Victoria), with most admissions represented by those above 40 years of age. Discussion There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.
Publisher: European Respiratory Society
Date: 04-09-2022
Publisher: The Korean Academy of Asthma, Allergy and Clinical Immunology and The Korean Academy of Pediatric Al
Date: 2021
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: Elsevier BV
Date: 03-2018
Publisher: Oxford University Press (OUP)
Date: 12-2008
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: Oxford University Press (OUP)
Date: 02-11-2017
Publisher: Springer Science and Business Media LLC
Date: 04-05-2022
DOI: 10.1038/S42003-022-03367-Z
Abstract: IL-25 is implicated in the pathogenesis of viral asthma exacerbations. However, the effect of IL-25 on antiviral immunity has yet to be elucidated. We observed abundant expression and colocalization of IL-25 and IL-25 receptor at the apical surface of uninfected airway epithelial cells and rhinovirus infection increased IL-25 expression. Analysis of immune transcriptome of rhinovirus-infected differentiated asthmatic bronchial epithelial cells (BECs) treated with an anti-IL-25 monoclonal antibody (LNR125) revealed a re-calibrated response defined by increased type I/III IFN and reduced expression of type-2 immune genes CCL26, IL1RL1 and IL-25 receptor. LNR125 treatment also increased type I/III IFN expression by coronavirus infected BECs. Exogenous IL-25 treatment increased viral load with suppressed innate immunity. In vivo LNR125 treatment reduced IL-25/type 2 cytokine expression and increased IFN-β expression and reduced lung viral load. We define a new immune-regulatory role for IL-25 that directly inhibits virus induced airway epithelial cell innate anti-viral immunity.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.PHARMTHERA.2016.11.003
Abstract: A common feature of chronic respiratory disease is the progressive decline in lung function. The decline can be indolent, or it can be accelerated by acute exacerbations, whereby the patient experiences a pronounced worsening of disease symptoms. Moreover, acute exacerbations may also be a marker of insufficient disease management. The underlying cause of an acute exacerbation can be due to insults such as pathogens or environmental pollutants, or the cause can be unknown. For each acute exacerbation, the patient may require medical intervention such as rescue medication, or in more severe cases, hospitalization and ventilation and have an increased risk of death. Biologics, such as monoclonal antibodies, are being developed for chronic respiratory diseases including asthma, COPD and IPF. This therapeutic approach is particularly well suited for chronic use based on the route and frequency of delivery and importantly, the potential for disease modification. In recent clinical trials, the frequency of acute exacerbation has often been included as an endpoint, to help determine whether the investigational agent is impacting disease. Therefore the significance of acute exacerbations in driving disease, and their potential as a marker of disease activity and progression, has recently received much attention. There is also now a need to standardize the definition of an acute exacerbation in specific disease settings, particularly as this endpoint is increasingly used in clinical trials to also assess therapeutic efficacy. Moreover, specifically targeting exacerbations may offer a new therapeutic approach for several chronic respiratory diseases.
Publisher: European Respiratory Society (ERS)
Date: 04-2020
DOI: 10.1183/23120541.00270-2019
Abstract: We aimed to assess adherence to the Australian national guideline (COPD-X) against audited practice, and to document the outcomes of patients hospitalised with an acute exacerbation of chronic obstructive pulmonary disease (COPD) at discharge and 28 days after. A prospective clinical audit of COPD hospital admission from five tertiary care hospitals in five states of Australia was conducted. Post-discharge follow-up was conducted via telephone to assess for readmission and health status. There were 207 admissions for acute exacerbation (171 patients mean 70.2 years old 50.3% males). Readmission rates at 28 days were 25.4%, with one (0.6%) death during admission and eight (6.1%) post-discharge within 28 days. Concordance to the COPD-X guidance was variable 22.7% performed spirometry, 81.1% had blood gases collected when forced expiratory volume in 1 s was L, 99.5% had chest radiography performed, 95.1% were prescribed systemic corticosteroids and 95% were prescribed antibiotic therapy. There were 89.1% given oxygen therapy and 92.6% when arterial oxygen tension was mmHg 65.6% were given ventilatory assistance when pH was .35. Only 32.4% were referred to pulmonary rehabilitation but 76.8% had general practitioner follow-up arranged. When compared against clinical practice guidelines, we found important gaps in management of patients admitted with COPD throughout tertiary care centres in Australia. Strategies to improve guideline uptake are needed to optimise care.
Publisher: European Respiratory Society (ERS)
Date: 07-2022
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: Springer Science and Business Media LLC
Date: 17-11-2022
DOI: 10.1038/S41598-022-24374-4
Abstract: Survival statistics, estimated using data from national cystic fibrosis (CF) registries, inform the CF community and monitor disease progression. This study aimed to estimate survival among people with CF in Australia and to identify factors associated with survival. This population-based cohort study used prospectively collected data from 23 Australian CF centres participating in the Australian CF Data Registry (ACFDR) from 2005–2020. Period survival analysis was used to calculate median age of survival estimates for each 5-year window from 2005–2009 until 2016–2020. The overall median survival was estimated using the Kaplan–Meier method. Between 2005–2020 the ACFDR followed 4,601 people with CF, noting 516 (11.2%) deaths including 195 following lung transplantation. Out of the total s le, more than half (52.5%) were male and 395 (8.6%) had undergone lung transplantation. Two thirds of people with CF (66.1%) were diagnosed before six weeks of age or by newborn renatal screening. The overall median age of survival was estimated as 54.0 years (95% CI: 51.0–57.04). Estimated median survival increased from 48.9 years (95% CI: 44.7–53.5) for people with CF born in 2005–2009, to 56.3 years (95% CI: 51.2–60.4) for those born in 2016–2020. Factors independently associated with reduced survival include receiving a lung transplant, having low FEV 1 pp and BMI. Median survival estimates are increasing in CF in Australia. This likely reflects multiple factors, including newborn screening, improvement in diagnosis, refinements in CF management and centre-based multidisciplinary care.
Publisher: BMJ
Date: 09-2014
Publisher: Rockefeller University Press
Date: 21-03-2005
DOI: 10.1084/JEM.20041901
Abstract: Rhinoviruses are the major trigger of acute asthma exacerbations and asthmatic subjects are more susceptible to these infections. To investigate the underlying mechanisms of this increased susceptibility, we examined virus replication and innate responses to rhinovirus (RV)-16 infection of primary bronchial epithelial cells from asthmatic and healthy control subjects. Viral RNA expression and late virus release into supernatant was increased 50- and 7-fold, respectively in asthmatic cells compared with healthy controls. Virus infection induced late cell lysis in asthmatic cells but not in normal cells. Examination of the early cellular response to infection revealed impairment of virus induced caspase 3/7 activity and of apoptotic responses in the asthmatic cultures. Inhibition of apoptosis in normal cultures resulted in enhanced viral yield, comparable to that seen in infected asthmatic cultures. Examination of early innate immune responses revealed profound impairment of virus-induced interferon-β mRNA expression in asthmatic cultures and they produced & .5 times less interferon-β protein. In infected asthmatic cells, exogenous interferon-β induced apoptosis and reduced virus replication, demonstrating a causal link between deficient interferon-β, impaired apoptosis and increased virus replication. These data suggest a novel use for type I interferons in the treatment or prevention of virus-induced asthma exacerbations.
Publisher: MDPI AG
Date: 23-12-2023
DOI: 10.3390/IJMS24010252
Abstract: Bifidobacterium are prominent gut commensals that produce the short-chain fatty acid (SCFA) acetate, and they are often used as probiotics. Connections between the gut and the lung, termed the gut–lung axis, are regulated by the microbiome. The gut–lung axis is increasingly implicated in cigarette smoke-induced diseases, and cigarette smoke exposure has been associated with depletion of Bifidobacterium species. In this study, we assessed the impact of acetate-producing Bifidobacterium longum subsp. longum (WT) and a mutant strain with an impaired acetate production capacity (MUT) on cigarette smoke-induced inflammation. The mice were treated with WT or MUT B. longum subsp. longum and exposed to cigarette smoke for 8 weeks before assessments of lung inflammation, lung tissue gene expression and cecal SCFAs were performed. Both strains of B. longum subsp. longum reduced lung inflammation, inflammatory cytokine expression and adhesion factor expression and alleviated cigarette smoke-induced depletion in caecum butyrate. Thus, the probiotic administration of B. longum subsp. longum, irrespective of its acetate-producing capacity, alleviated cigarette smoke-induced inflammation and the depletion of cecal butyrate levels.
Publisher: Cold Spring Harbor Laboratory
Date: 12-04-2023
DOI: 10.1101/2023.04.12.536514
Abstract: Primary air liquid interface (ALI) cultures of bronchial epithelial cells are used extensively to model airway responses. A recent advance is the development of conditional reprogramming that enhances proliferative capability. Several different media and protocols are utilized, yet even subtle differences may influence cellular responses. We compared the morphology and functional responses, including innate immune responses to rhinovirus infection in conditionally reprogrammed primary bronchial epithelial cells (pBECs) differentiated using two commonly used culture media. pBECs from healthy participants (n = 5) were CR using γ-irradiated 3T3 fibroblasts and Rho Kinase inhibitor. CRpBECs were differentiated at ALI in either PneumaCult™ (PN-ALI) or Bronchial Epithelial Growth Medium (BEGM)-based differentiation media (BEBM:DMEM, 50:50, Lonza™) - (AB-ALI) for 28 days. Transepithelial electrical resistance (TEER), immunofluorescence, histology, cilia activity, ion channel function, and expression of cell markers were analyzed. Viral load was assessed by RT-qPCR and anti-viral factors quantified by Legendplex following Rhinovirus-A1b (RVA1b) infection. CRpBECs differentiated in PneumaCult™ were smaller and had a lower TEER and cilia beat frequency (CBF) compared to BEGM media. PneumaCult™ media cultures exhibited significantly increased FOXJ1 expression, more ciliated cells with a larger active area, increased intracellular mucins, and increased calcium-activated chloride channel current. However, there were no significant changes in viral RNA or host antiviral responses. There are distinct structural and functional differences in CRpBECs cultured in the two commonly used ALI differentiation media. Such factors need to be taken into consideration when designing and comparing CRpBECs ALI experiments.
Publisher: Elsevier BV
Date: 03-2013
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: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.VACCINE.2015.10.016
Abstract: We provide estimates of the influenza vaccine protection against hospitalisation with laboratory-confirmed influenza in the 2014 Australian season where the A/H1N1 dm09 strain predominated. This was performed using a case-test negative study design as part of a national sentinel surveillance system in Australia. Vaccine effectiveness was estimated as (1-OR)×100% where the odds ratio of vaccination in cases vs test negative participants was estimated from a conditional logistic regression. Between April and November, 1692 adult patients were admitted with laboratory-confirmed influenza. Vaccine effectiveness was estimated from 1283 patients with influenza and 1116 test negative patients where vaccination status was ascertained. Vaccination was associated with a reduction in the risk of hospitalisation with influenza of 51.5% (95% CI: 41.6%, 59.7%) in all patients, and a reduction of 50.7% (95% CI: 40.1%, 59.3%) in the target population for vaccination. We estimate that the influenza vaccine was moderately protective against hospitalisation with laboratory-confirmed influenza during the 2014 influenza season in Australia.
Publisher: eLife Sciences Publications, Ltd
Date: 27-06-2019
DOI: 10.7554/ELIFE.42448
Abstract: Although respiratory syncytial virus (RSV) is responsible for more human deaths each year than influenza, its pathogenic mechanisms are poorly understood. Here high-resolution quantitative imaging, bioenergetics measurements and mitochondrial membrane potential- and redox-sensitive dyes are used to define RSV’s impact on host mitochondria for the first time, delineating RSV-induced microtubule/dynein-dependent mitochondrial perinuclear clustering, and translocation towards the microtubule-organizing centre. These changes are concomitant with impaired mitochondrial respiration, loss of mitochondrial membrane potential and increased production of mitochondrial reactive oxygen species (ROS). Strikingly, agents that target microtubule integrity the dynein motor protein, or inhibit mitochondrial ROS production strongly suppresses RSV virus production, including in a mouse model with concomitantly reduced virus-induced lung inflammation. The results establish RSV’s unique ability to co-opt host cell mitochondria to facilitate viral infection, revealing the RSV-mitochondrial interface for the first time as a viable target for therapeutic intervention.
Publisher: American Physiological Society
Date: 12-2019
DOI: 10.1152/AJPLUNG.00253.2019
Abstract: Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in s les from patients with COPD at stable state and during virus-associated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) s led from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators ( exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the antiviral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cell-intrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro rhinovirus (RV) infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 wk following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention and treatment of frequent exacerbations.
Publisher: Informa UK Limited
Date: 10-01-2014
DOI: 10.1586/17476348.2014.848795
Abstract: The rising prevalence of asthma and atopic disease in industrialized countries in the last 50 years has raised important questions about how and why the disease develops in susceptible populations. Most asthma begins in childhood in association with allergic sensitization and the development of a TH2 phenotype. It is recognized that asthma arises in the context of a complex interaction between genetic factors and the evolving immune system of the infant and the environment to which it is exposed, which now includes its in utero exposure. Early life exposures that lead to allergen sensitization and airway damage, especially in the form of viral respiratory tract infections, may lead to disease induction that commence the process that leads in some to asthma. Asthma models and early life observations suggest that repeated exposure to allergens and viral infection perpetuate a state of chronic airway inflammation leading to a maladaptive innate immune response that fails to resolve, characterized by chronic airway inflammation, airway remodeling and airway hyperresponsiveness. This article will concentrate on the development of asthma in the context of early life and maternal influences, including the effect of asthma on both the fetus and the mother.
Publisher: Elsevier BV
Date: 04-2003
Publisher: European Respiratory Society (ERS)
Date: 23-06-2016
DOI: 10.1183/13993003.00436-2016
Abstract: Patients with asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS) have been largely excluded from pivotal therapeutic trials and, as a result, its treatment remains poorly defined and lacking firm evidence. To date, there is no universally accepted definition of ACOS, which has made it difficult to understand its epidemiology or pathophysiology. Despite many uncertainties, there is emerging agreement that some of the key features of ACOS include persistent airflow limitation in symptomatic in iduals 40 years of age and older, a well-documented history of asthma in childhood or early adulthood and a significant exposure history to cigarette or biomass smoke. In this perspective, we propose a case definition of ACOS that incorporates these key features in a parsimonious algorithm that may enable clinicians to better diagnose patients with ACOS and most importantly enable researchers to design therapeutic and clinical studies to elucidate its epidemiology and pathophysiology and to ascertain its optimal management strategies.
Publisher: Cambridge University Press (CUP)
Date: 07-2009
DOI: 10.1017/S0007114508019880
Abstract: Prebiotics are food ingredients that improve health by modulating the colonic microbiota. The bifidogenic effect of the prebiotic inulin is well established however, it remains unclear which species of Bifidobacterium are stimulated in vivo and whether bacterial groups other than lactic acid bacteria are affected by inulin consumption. Changes in the faecal microbiota composition were examined by real-time PCR in twelve human volunteers after ingestion of inulin (10 g/d) for a 16-d period in comparison with a control period without any supplement intake. The prevalence of most bacterial groups examined did not change after inulin intake, although the low G+C % Gram-positive species Faecalibacterium prausnitzii exhibited a significant increase (10·3 % for control period v. 14·5 % during inulin intake, P = 0·019). The composition of the genus Bifidobacterium was studied in four of the volunteers by clone library analysis. Between three and five Bifidobacterium spp. were found in each volunteer. Bifidobacterium adolescentis and Bifidobacterium longum were present in all volunteers, and Bifidobacterium pseudocatenulatum , Bifidobacterium animalis , Bifidobacterium bifidum and Bifidobacterium dentium were also detected. Real-time PCR was employed to quantify the four most prevalent Bifidobacterium spp., B. adolescentis , B. longum , B. pseudocatenulatum and B. bifidum , in ten volunteers carrying detectable levels of bifidobacteria. B. adolescentis showed the strongest response to inulin consumption, increasing from 0·89 to 3·9 % of the total microbiota ( P = 0·001). B. bifidum was increased from 0·22 to 0·63 % ( P 0·001) for the five volunteers for whom this species was present.
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: American Physiological Society
Date: 10-2022
DOI: 10.1152/AJPLUNG.00137.2022
Abstract: Management of patients with asthma COPD overlap (ACO) is clinically challenging due to insufficient evidence of pathological changes in these patients. In this cross-sectional study, we evaluated airway remodeling in endobronchial biopsies from a total of 90 subjects, which included 12 ACO, 14 patients with asthma, 12 COPD exsmokers (ES), 11 current smokers (CS), 28 healthy controls (HC), and 13 normal lung function smokers (NLFS). Tissue was stained with Masson’s trichrome. Epithelium, goblet cells, reticular basement membrane (RBM), cellularity, lamina propria (LP), and smooth muscle (SM) changes were measured using Image-Pro Plus v7 software. Differential airway remodeling pattern was seen in patients with ACO. A limited change was noted in the ACO epithelium compared with other pathological groups. RBM was substantially thicker in patients with ACO than in HC ( P 0.0002) and tended to be thicker than in patients with asthma and NLFS. The total RBM cells were higher in ACO than in the HC ( P 0.0001), COPD-CS ( P = 0.0559), -ES ( P = 0.0345), and NLFS ( P 0.0002), but did not differ from patients with asthma. Goblet cells were higher in the ACO than in the HC ( P = 0.0028) and COPD-ES ( P = 0.0081). The total LP cells in ACO appeared to be higher than in HC, COPD-CS, and NLFS but appeared to be lower than in patients with asthma. Finally, SM area was significantly lower in the ACO than in patients with asthma ( P = 0.001), COPD-CS (=0.0290), and NLFS ( P = 0.0011). This first comprehensive study suggests that patients with ACO had distinguishable tissue remodeling that appeared to be more severe than patients with asthma and COPD. This study will help in informed decision-making for better patient management in clinical practice.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2019
Publisher: MDPI AG
Date: 29-03-2017
DOI: 10.3390/NU9040341
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: European Respiratory Society (ERS)
Date: 04-2020
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Wiley
Date: 30-10-2020
DOI: 10.1111/RESP.13722
Abstract: COPD is a seriously disabling respiratory condition that inexorably progresses to disability and mortality. It affects approximately 10% of the population globally with a greater prevalence at advanced ages. Airway bacterial infections complicate the disease course in most COPD patients, leading to increased symptoms, more rapid decline in lung function, acute exacerbations and reduced quality of life. With increasing bacterial resistance to antibiotics and adverse effects of conventional treatments, new effective non-antibiotic antimicrobial therapies are urgently needed to manage COPD. Hypoxia-inducible factor (HIF)-1α is an important transcriptional regulator of cellular responses to hypoxia, oxidants and inflammation, and is overexpressed in the lungs of COPD patients. Recent evidence shows that increased HIF-1α expression can upregulate the platelet-activating factor receptor (PAFR) on the airway epithelial surface that is increased in smokers and particularly COPD patients. The receptor is utilized by PAFR-dependent bacteria (Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa) to induce infection in both the respiratory and gastrointestinal (GI) tracts. However, the importance and mechanism of HIF-1α in augmenting PAFR-dependent bacterial infections in COPD are poorly understood. Here, we review the evidence for the roles of local tissue hypoxia-induced inflammation, HIF-1α and PAFR in facilitating bacterial infections in COPD. Blocking PAFR may provide a novel antimicrobial approach to manage bacterial infections in COPD.
Publisher: Elsevier BV
Date: 02-2018
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.JRI.2014.09.051
Abstract: Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still being capable of inducing an immune response against invading pathogens. To achieve this, numerous changes must occur in the activity and function of maternal immune cells throughout the course of pregnancy. Respiratory viruses take advantage of these changes, altering the sensitive balance of maternal immunity, leaving the mother with increased susceptibility to viral infections and increased disease severity. Influenza virus is one of the most common respiratory virus infections during pregnancy, leading to an increased risk of ICU hospitalisations, pneumonia, acute respiratory distress syndrome and even death. Whilst much research has been performed to understand the changes that must take place in maternal immunity during pregnancy, considerable work is still needed to fully comprehend this tremendous feat. To date, few studies have focused on the alterations that occur in maternal immunity during respiratory virus infections. This review highlights the role of dendritic cells (DCs) and CD8 T cells during pregnancy, and the changes that occur in these antiviral cells following influenza virus infections.
Publisher: American Thoracic Society
Date: 03-2023
Publisher: Springer Science and Business Media LLC
Date: 13-08-2006
DOI: 10.1038/NM1462
Abstract: Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.
Publisher: SAGE Publications
Date: 08-2018
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.PHARMTHERA.2017.12.009
Abstract: Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, therapeutic strategies to reduce mucus accumulation have focused primarily on altering the properties of the mucus itself, or have aimed to limit the production of mucus-stimulating cytokines. Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation and highlights both pre-existing and novel therapeutic strategies to combat this pathology.
Publisher: European Respiratory Society
Date: 09-2015
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Informa UK Limited
Date: 10-2017
DOI: 10.2147/COPD.S136256
Publisher: Elsevier BV
Date: 09-2007
Publisher: Oxford University Press (OUP)
Date: 15-07-2013
Abstract: Pregnant women are a high-risk group during influenza pandemics. In this study we determined whether plasmacytoid dendritic cells (pDCs) and CD8 T cells from pregnant women display altered activity following in vitro infection with 2009 pandemic swine influenza (H1N1/09). Peripheral blood mononuclear cells (PBMCs) were isolated from pregnant (n = 26) and nonpregnant (n = 28) women. DC subtypes were enumerated from PBMCs. PBMCs were infected with H1N1/09 and CD86, human leukocyte antigen-DR (HLA-DR), and programmed death ligand 1/2 (PDL1/2) measured on pDCs. PD receptor 1 (PD1) was measured on CD8 T cells. Interferon-alpha (IFN-α), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNFα), and IFN-gamma were measured from culture supernatant. pDC (ie, CD303(+)/CD1c(-) PBMCs) percentages were lower in pregnant compared with nonpregnant women (P < .05). Following H1N1/09 infection, pDCs from pregnant women showed higher expression of CD86 (P < .01), HLA-DR (P < .001), and PDL1 (P < .001) compared with nonpregnant women. Expression of PD1 on CD8 T cells was higher during pregnancy (P < .05). Following H1N1/09 infection, PBMCs from pregnant women displayed reduced IFN-α (P < .01), IL-2 (P < .01), and IFN-γ (P < .01) compared with nonpregnant women. Blocking PDL1 during H1N1/09 infection increased these cytokines during pregnancy (P < .05). Altered maternal cellular antiviral activity is implicated in the increased morbidity during pregnancy following influenza pandemics.
Publisher: SAGE Publications
Date: 30-06-2004
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: European Respiratory Society (ERS)
Date: 10-2002
DOI: 10.1183/09031936.02.00192002
Abstract: Infection with Chlamydia pneumoniae can trigger acute asthma and is associated with severe chronic asthma. The aim of the present study was to examine the relationship between airway inflammation and serological response to C. pneumoniae in acute severe asthma. Subjects (n=54) were recruited within 4 h of presentation to the emergency department with an acute exacerbation of asthma. Clinical history taking, sputum induction (0.9% saline), spirometry and acute and convalescent serology for C. pneumoniae immunoglobulins A and G were performed. At presentation, 47% of subjects had antibodies directed against C. pneumoniae, and 38% (20) demonstrated an increase in C. pneumoniae antibody levels, with 15 demonstrating a rise in immunoglobulin A concentration. C. pneumoniae responders exhibited significantly higher sputum neutrophil levels (4.6 x 10(6) cells x mL(-1)) compared to nonresponders (1.2 x 10(6) cells x mL(-1), p=0.02) and elevated sputum eosinophil cationic protein concentration (3,981 versus 1,122 ng x mL(-1), p=0.02). An acute antibody response to Chlamydia pneumoniae is common in exacerbations of asthma. The serological features suggest that Chlamydia pneumoniae reactivation may trigger neutrophilic airway inflammation in acute asthma.
Publisher: Elsevier BV
Date: 11-2014
Publisher: European Respiratory Society
Date: 09-2015
Publisher: Springer Science and Business Media LLC
Date: 02-08-2018
Publisher: European Respiratory Society
Date: 09-2017
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: Oxford University Press (OUP)
Date: 27-09-2019
Abstract: Pulmonary inflammation in chronic obstructive pulmonary disease (COPD) is characterized by both innate and adaptive immune responses however, their specific roles in the pathogenesis of COPD are unclear. Therefore, we investigated the roles of T and B lymphocytes and group 2 innate lymphoid cells (ILC2s) in airway inflammation and remodelling, and lung function in an experimental model of COPD using mice that specifically lack these cells (Rag1−/− and Rorafl/flIl7rCre [ILC2-deficient] mice). Wild-type (WT) C57BL/6 mice, Rag1−/−, and Rorafl/flIl7rCre mice were exposed to cigarette smoke (CS 12 cigarettes twice a day, 5 days a week) for up to 12 weeks, and airway inflammation, airway remodelling (collagen deposition and alveolar enlargement), and lung function were assessed. WT, Rag1−/−, and ILC2-deficient mice exposed to CS had similar levels of airway inflammation and impaired lung function. CS exposure increased small airway collagen deposition in WT mice. Rag1−/− normal air- and CS-exposed mice had significantly increased collagen deposition compared to similarly exposed WT mice, which was associated with increases in IL-33, IL-13, and ILC2 numbers. CS-exposed Rorafl/flIl7rCre mice were protected from emphysema, but had increased IL-33/IL-13 expression and collagen deposition compared to WT CS-exposed mice. T/B lymphocytes and ILC2s play roles in airway collagen deposition/fibrosis, but not inflammation, in experimental COPD. T/B lymphocytes and ILC2s play roles in airway fibrosis but not inflammation in a mouse model of experimental COPD.
Publisher: Wiley
Date: 17-07-2021
DOI: 10.1111/CEA.13986
Abstract: Severe asthma is a complex disease. Transcriptomic profiling has contributed to understanding the pathogenesis of asthma, especially type‐2 inflammation. However, there is still poor understanding of non‐type‐2 asthma, and consequently, there are limited treatment options. The aim of this study was to identify differentially expressed genes (DEGs) and pathways in endobronchial biopsies associated with inflammatory phenotypes of severe asthma. This cross‐sectional study examined endobronchial biopsies from 47 adults with severe asthma (neutrophilic asthma (NA) n = 9, eosinophilic asthma (EA) n = 22 and paucigranulocytic asthma (PGA) n = 16) and 13 healthy controls (HC). RNA was extracted and transcriptomic profiles generated (Illumina Humanref‐12 V4) and analysed using GeneSpring GX14.9.1. Pathway identification using Ingenuity Pathway Analysis. NA had the most distinct profile, with signature of 60 top‐ranked DEGs (FC ±2) including genes associated with innate immunity response, neutrophil degranulation and IL‐10 signalling. NA presented enrichment to pathways previously linked to neutrophilic inflammation dendritic cell maturation, Th1, TREM1, inflammasome, Th17 and p38 MAPK, as well as novel links to neuroinflammation, NFAT and PKCθ signalling. EA presented similar transcriptomic profiles to PGA and HC. Despite the higher proportion of bacterial colonization in NA, no changes were observed in the transcriptomic profiles of severe asthma culture positive compared with severe asthma culture negative. NA features a distinct transcriptomic profile with seven pathways enriched in NA compared to EA, PGA and HC. All those with severe asthma had significant enrichment for SUMOylation, basal cell carcinoma signalling and Wnt/β‐catenin pathways compared to HC, despite high‐dose inhaled corticosteroids. These findings contribute to the understanding of mechanistic pathways in endobronchial biopsies associated with NA and identify potential novel treatment targets for severe asthma.
Publisher: Wiley
Date: 04-2021
DOI: 10.1002/RCR2.742
Publisher: Oxford University Press (OUP)
Date: 09-06-2023
DOI: 10.1093/CID/CIAC453
Abstract: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.
Publisher: BMJ
Date: 14-01-2016
DOI: 10.1136/THORAXJNL-2014-206716
Abstract: The mucoactive effects of hypertonic saline should promote exacerbation resolution in people with cystic fibrosis (CF). To determine the effects of hypertonic saline inhalation during hospitalisation for exacerbation of CF on length of stay, lung function, symptoms, oxygenation, exercise tolerance, quality of life, bacterial load and time to next hospitalisation. 132 adults with an exacerbation of CF were randomised to inhale three nebulised doses a day of either 4 mL 7% saline or a taste-masked control of 0.12% saline, throughout the hospital admission. The primary outcome measure was length of hospital stay. All participants tolerated their allocated saline solution. There was no significant difference in length of stay, which was 12 days in the hypertonic saline group and 13 days in controls, with a mean between-group difference (MD) of 1 day (95% CI 0 to 2). The likelihood of regaining pre-exacerbation FEV1 by discharge was significantly higher in the hypertonic saline group (75% vs 57%), and the number needed to treat was 6 (95% CI 3 to 65). On a 0-100 scale, the hypertonic saline group had significantly greater reduction in symptom severity than the control group at discharge in sleep (MD=13, 95% CI 4 to 23), congestion (MD=10, 95% CI 3 to 18) and dyspnoea (MD=8, 95% CI 1 to 16). No significant difference in time to next hospitalisation for a pulmonary exacerbation was detected between groups (HR=0.86 (CI 0.57 to 1.30), p=0.13). Other outcomes did not significantly differ. Addition of hypertonic saline to the management of a CF exacerbation did not reduce the length of hospital stay. Hypertonic saline speeds the resolution of exacerbation symptoms and allows patients to leave hospital with greater symptom resolution. ACTRN12605000780651.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Wiley
Date: 03-2001
DOI: 10.1046/J.1440-1843.2001.00289.X
Abstract: Allergic bronchopulmonary aspergillosis (ABPA) is a condition that results from a hypersensitivity reaction to the fungus Aspergillus fumigatus. The purpose of the present review is to examine the pathogenesis of this condition and the evidence for treatments available. Allergic bronchopulmonary aspergillosis is characterized by an intense airway inflammation with eosinophils and the formation of mucus plugs. Clinically, there are periods of exacerbation and remission that may lead to proximal bronchiectasis and fibrotic lung disease. New evidence confirms the role of intense airway inflammation with eosinophils, but also suggests a role for interleukin (IL)-8/neutrophil-mediated inflammation in this process, and the potential deficiency of anti-inflammatory cytokines such as reduced IL-10. Treatment for ABPA has so far focused on corticosteroids to suppress eosinophilic airway inflammation. An expanding knowledge of the pathology of ABPA also suggests other therapies may be of potential benefit, particularly the use of azole antifungal agents. Allergic bronchopulmonary aspergillosis is itself an important complication of asthma and cystic fibrosis. A greater understanding of the condition is required to improve management and well-designed clinical trials need to be carried out to critically assess new and current treatments. In addition, the information gained from the studies of its pathogenesis has the potential to benefit our understanding of the disease processes in asthma and bronchiectasis.
Publisher: Australian Government Department of Health
Date: 16-09-2019
Abstract: The Influenza Complications Alert Network (FluCAN) is a sentinel-hospital-based surveillance program that operates at sites in all jurisdictions in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2017 influenza season. In this observational surveillance system, cases were defined as patients admitted to any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data are also collected on a frequency-matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 3 April to 31 October 2017 (the 2017 influenza season), 4,359 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 52% were elderly (≥65 years), 14% were children ( years), 6.5% were Aboriginal and Torres Strait Islander peoples, 1.6% were pregnant and 78% had chronic comorbidities. A significant proportion were due to influenza B (31%). Estimated vaccine coverage was 72% in the elderly (≥65 years), 50% in non-elderly adults with medical comorbidities and 24% in children ( years) with medical comorbidities. The estimated vaccine effectiveness (VE) in the target population was 23% (95% CI: 7%, 36%). There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2017, with case numbers more than twice that reported in 2016.
Publisher: Public Library of Science (PLoS)
Date: 02-03-2012
Publisher: European Respiratory Society
Date: 04-09-2022
Publisher: Public Library of Science (PLoS)
Date: 04-2015
Publisher: American Society for Clinical Investigation
Date: 16-06-2016
Publisher: Wiley
Date: 25-07-2013
DOI: 10.1111/RESP.12099
Publisher: Wiley
Date: 30-10-2008
Publisher: Elsevier BV
Date: 05-2018
Publisher: Informa UK Limited
Date: 06-2008
Abstract: Airway inflammation is central to the development and progression of asthma. Monitoring airway inflammation can be invasive and technically difficult, making its use limited in clinical practice. Several advances have been made in non-invasive techniques to monitor and measure inflammation from the airways. To examine the suitability of exhaled nitric oxide and exhaled breath condensates as diagnostic tools in asthma. The current literature regarding the use of exhaled nitric oxide and exhaled breath condensate to assess and manage asthma was reviewed. Exhaled nitric oxide is a clinically useful marker of eosinophilic airway inflammation in asthma. Although showing promise, significant validation and investigation are required before exhaled breath condensate could be utilized in clinical practice.
Publisher: Wiley
Date: 14-07-2021
DOI: 10.1111/CEA.13979
Abstract: A high fruit and vegetable (F& V) diet reduces asthma exacerbations in adults this has not been examined in children to date. To investigate the effect of a 6‐month, high F& V diet on the time to first asthma exacerbation in children with asthma, in a parallel‐group, randomized, controlled trial. Children (aged 3–11 years) with asthma, history of exacerbations and usual low F& V intake (≤3 serves/day) were randomized to the intervention (high F& V diet) or control group (usual diet) for 6 months. The primary outcome was time to first exacerbation requiring medical intervention. Secondary outcomes included exacerbation rate, lung function, plasma TNF‐α, CRP, and IL‐6, faecal microbiota and peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity and G‐protein coupled receptor (GPR) 41/43 and HDAC (1–11) expression. 67 children were randomized between September 2015 and July 2018. F& V intake (difference in change (∆): 3.5 serves/day, 95% CI: [2.6, 4.4] p 0.001) and plasma total carotenoids (∆: 0.44 µg/ml [0.19, 0.70] p = 0.001) increased after 6 months (intervention vs control). Time to first exacerbation (HR: 0.81, 95% CI: [0.38, 1.69], p = 0.569 control vs. intervention) and exacerbation rate (IRR: 0.84, [0.47, 1.49], p = 0.553 control vs. intervention) were similar between groups. In per‐protocol analysis, airway reactance z‐scores increased in the intervention versus control group ( X 5 ∆: 0.76 [0.04, 1.48] p = 0.038, X 20 ∆: 0.93 [0.23, 1.64] p = 0.009) and changes in faecal microbiota were observed though there was no difference between groups in systemic inflammation or molecular mechanisms. In the control group, CRP and HDAC enzyme activity increased, while GPR41 expression decreased. No adverse events attributable to the interventions were observed. A high F& V diet did not affect asthma exacerbations over the 6‐month intervention, though warrants further investigation as a strategy for improving lung function and protecting against systemic inflammation in children with asthma.
Publisher: Oxford University Press (OUP)
Date: 21-08-2019
DOI: 10.1093/CID/CIY597
Abstract: In 2017, Australia experienced record influenza notifications. Two surveillance programs combined to summarize the epidemiology of hospitalized influenza in children and report on vaccine effectiveness (VE) in the context of a limited nationally funded vaccination program. Subjects were prospectively recruited (April-October 2017). Case patients were children aged ≤16 years admitted to 11 hospitals with an acute respiratory illness and laboratory-confirmed influenza. Controls were hospitalized with acute respiratory illness and tested negative for influenza. VE estimates were calculated using the test-negative design. A total of 1268 children were hospitalized with influenza: 31.5% were <2 years old, 8.3% were indigenous, and 45.1% had comorbid conditions predisposing to severe influenza. Influenza B was detected in 34.1% with influenza A/H1N1 and A/H3N2 detected in 47.2% and 52.8% of subtyped influenza A specimens. The median length of stay was 3 days (interquartile range, 1-5), 14.5% were admitted to the intensive care unit, and 15.9% received oseltamivir. Four in-hospital deaths occurred (0.3%): one was considered influenza associated. Only 17.1% of test-negative-controls were vaccinated. The VE of inactivated quadrivalent influenza vaccine for preventing hospitalized influenza was estimated at 30.3% (95% confidence interval, 2.6%-50.2%). Significant influenza-associated morbidity was observed in 2017 in Australia. Most hospitalized children had no comorbid conditions. Vaccine coverage and antiviral use was inadequate. Influenza vaccine was protective in 2017, yet VE was lower than previous seasons. Multiple Australian states have introduced funded preschool vaccination programs in 2018. Additional efforts to promote vaccination and monitor effectiveness are required.
Publisher: Wiley
Date: 06-12-2020
DOI: 10.1111/RESP.13749
Abstract: Severe asthma is responsible for a disproportionate burden of illness and healthcare costs spent on asthma. This study analyses sputum transcriptomics to investigate the mechanisms and novel treatment targets of severe asthma. Induced sputum s les were collected in a cross-sectional study from participants with severe asthma (n = 12, defined as per GINA criteria), non-severe uncontrolled (n = 21) and controlled asthma (n = 21) and healthy controls (n = 15). Sputum RNA was extracted and transcriptomic profiles were generated (Illumina HumanRef-8 V2) and analysed (GeneSpring). Sputum protein lysates were analysed for p38 activation in a validation study (n = 24 asthma, n = 8 healthy) by western blotting. There were 2166 genes differentially expressed between the four groups. In severe asthma, the expression of 1875, 1308 and 563 genes was altered compared to healthy controls, controlled and uncontrolled asthma, respectively. Of the 1875 genes significantly different to healthy controls, 123 were >2-fold change from which four networks were identified. Thirty genes (>2-fold change) were significantly different in severe asthma compared to both controlled asthma and healthy controls. There was enrichment of genes in the p38 signalling pathway that were associated with severe asthma. Phosphorylation of p38 was increased in a subset of severe asthma s les, correlating with neutrophilic airway inflammation. Severe asthma is associated with substantial differences in sputum gene expression that underlie unique cellular mechanisms. The p38 signalling pathway may be important in the pathogenesis of severe asthma, and future investigations into p38 inhibition are warranted as a 'non-Th2' therapeutic option.
Publisher: Wiley
Date: 18-01-2018
DOI: 10.1002/RCR2.295
Publisher: Cambridge University Press (CUP)
Date: 17-07-2009
DOI: 10.1017/S0007114508025798
Abstract: Long-chain n -3 PUFA (LC n -3PUFA) including DHA and EPA, are known to decrease inflammation by inhibiting arachidonic acid (AA) metabolism to eicosanoids, decreasing the production of pro-inflammatory cytokines and reducing immune cell function. The aim of this study was to determine if EPA and DHA reduced the release of inflammatory mediators from airway epithelial cells infected with rhinovirus (RV). Airway epithelial cells (Calu-3) were incubated with EPA, DHA and AA for 24 h, followed by rhinovirus infection for 48 h. IL-6, IL-8 and interferon-γ-induced protein-10 (IP-10) released by cells were measured using ELISA. Viral replication was measured by serial titration assays. The fatty acid content of cells was analysed using GC. Cellular viability was determined by visual inspection of cells and lactate dehydrogenase release. DHA (400 μ m ) resulted in a significant 16 % reduction in IL-6 release after RV-43 infection, 29 % reduction in IL-6 release after RV-1B infection, 28 % reduction in IP-10 release after RV-43 infection and 23 % reduction in IP-10 release after RV-1B infection. Cellular DHA content negatively correlated with IL-6 and IP-10 release. None of the fatty acids significantly modified rhinovirus replication. DHA supplementation resulted in increased cellular content of DHA at the cost of AA, which may explain the decreased inflammatory response of cells. EPA and AA did not change the release of inflammatory biomarkers significantly. It is concluded that DHA has a potential role in suppressing RV-induced airway inflammation.
Publisher: European Respiratory Society (ERS)
Date: 08-07-2021
Publisher: Springer Science and Business Media LLC
Date: 08-06-2018
DOI: 10.1038/S41467-018-04574-1
Abstract: Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor ( IFNAR1 −/− ) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1038/MI.2015.111
Abstract: Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Australian Government Department of Health
Date: 18-11-2019
Abstract: The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2018 influenza season. In this observational surveillance system, cases were defined as patients admitted to any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data were also collected on a frequency-matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 3 April to 31 October 2018 (the 2018 influenza season), 769 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 30% were elderly (≥65 years), 28% were children ( years), 6.4% were Aboriginal and Torres Strait Islander peoples, 2.2% were pregnant and 66% had chronic comorbidities. A small proportion of FluCAN admissions were due to influenza B (13%). Estimated vaccine coverage was 77% in the elderly (≥65 years), 45% in non-elderly adults with medical comorbidities and 26% in children ( years) with medical comorbidities. The estimated vaccine effectiveness (VE) in the target population was 52% (95% CI: 37%, 63%). There were a smaller number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2018 than in 2017, with the demographic profile reflecting the change in circulating subtype from A/H3N2 to A/H1N1.
Publisher: Georg Thieme Verlag KG
Date: 02-2018
Abstract: Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus infection and asthma has long been recognized, though remains incompletely understood. In this article, we will address key issues around this relationship. These will include the crucial role virus infection plays in early life, as a potential risk factor for the development of asthma and lung disease. We will assess the impact that virus infection has on those with established asthma as a trigger for acute disease and how this may influence asthma throughout life. Finally, we will explore the complex interaction that occurs between the airway and the immune responses that make those with asthma so susceptible to the effects of virus infection.
Publisher: European Respiratory Society (ERS)
Date: 13-06-2019
DOI: 10.1183/13993003.00174-2018
Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis. Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients. However, its roles in the pathogenesis of COPD is poorly understood. Here, we investigated the role of IL-22 in human COPD and in cigarette smoke (CS)-induced experimental COPD. IL-22 and IL-22 receptor mRNA expression and protein levels were increased in COPD patients compared to healthy smoking or non-smoking controls. IL-22 and IL-22 receptor levels were increased in the lungs of mice with experimental COPD compared to controls and the cellular source of IL-22 included CD4 + T-helper cells, γδ T-cells, natural killer T-cells and group 3 innate lymphoid cells. CS-induced pulmonary neutrophils were reduced in IL-22-deficient ( Il22 −/− ) mice. CS-induced airway remodelling and emphysema-like alveolar enlargement did not occur in Il22 −/− mice. Il22 −/− mice had improved lung function in terms of airway resistance, total lung capacity, inspiratory capacity, forced vital capacity and compliance. These data highlight important roles for IL-22 and its receptors in human COPD and CS-induced experimental COPD.
Publisher: American Physiological Society
Date: 09-2023
DOI: 10.1152/AJPLUNG.00232.2022
Abstract: Influenza A virus (IAV) infection during pregnancy with asthma is a major health concern leading to increased morbidity for both mother and baby. Using murine models, we show that IAV infection in pregnancy with allergic airway disease is associated with impaired global antiviral and antimicrobial responses, increased lung inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). Targeting specific β-defensins or microRNAs (miRNAs) may prove useful in future treatments for IAV infection during pregnancy.
Publisher: AMPCo
Date: 21-07-2021
DOI: 10.5694/MJA2.51183
Publisher: Informa UK Limited
Date: 08-06-2019
DOI: 10.1080/02770903.2018.1471709
Abstract: Asthma exacerbations and medication non-adherence are significant clinical problems during pregnancy. While asthma self-management education is effective, the number of education sessions required to maximise asthma management knowledge and inhaler technique and whether improvements persist postpartum, are unknown. This paper describes how asthma knowledge, skills, and inhaled corticosteroid (ICS) use have changed over time. Data were obtained from 3 cohorts of pregnant women with asthma recruited in Newcastle, Australia between 2004 and 2017 (N = 895). Medication use, adherence, knowledge, and inhaler technique were compared between cohorts. Changes in self-management knowledge/skills and women's perception of medication risk to the fetus were assessed in 685 women with 5 assessments during pregnancy, and 95 women who had a postpartum assessment. At study entry, 41%, 29%, and 38% of participants used ICS in the 2004, 2007, and 2013 cohorts, respectively (p = 0.017), with 40% non-adherence in each cohort. Self-management skills of pregnant women with asthma did not improve between 2004 and 2017 and possession of a written action plan remained low. Maximum improvements were reached by 3 sessions for medications knowledge and one session for inhaler technique, and were maintained postpartum. ICS adherence was maximally improved after one session, but not maintained postpartum. Perceived risk of asthma medications on the fetus was highest for corticosteroid-containing medication and was significantly reduced following education. There was a high prevalence of non-adherence and poor self-management skills in all cohorts. More awareness of the importance of optimal asthma management during pregnancy is warranted, since no improvements were observed over the past decade.
Publisher: American Thoracic Society
Date: 08-2017
Publisher: Informa UK Limited
Date: 25-03-2016
DOI: 10.1586/17476348.2016.1165096
Abstract: Severe asthma is recognised as an important and emerging area of unmet need in asthma. The assessment of severe asthma should include three steps (1) determining the diagnosis of asthma, including verification that the disease is severe asthma, (2) assessing comorbidities and contributing factors that will impact on clinical severity, as well as (3) assessing asthma phenotypes. These steps recognize the importance of heterogeneity in asthma as a key factor that determines the disease course and increasingly the choice of successful therapy. This assessment should be undertaken systematically and is best done by an expert multidisciplinary team. Here, we will outline the important aspects that should be included in the clinical assessment of the patient in the severe asthma clinic, including diagnosis, clinical history, the assessment of important comorbidities and the key investigations needed to support them.
Publisher: Informa UK Limited
Date: 04-2010
DOI: 10.1586/ERS.10.5
Abstract: Respiratory tract infections are the most common infectious illnesses that afflict humans. In general, viral infections of the upper respiratory tract result in mild self-limiting symptoms. However, more serious lower respiratory tract infections can lead to the development of pneumonia. While viral infections alone may cause pneumonia, it is increasingly clear that they also play an important role in increasing the risk of bacterial infection and have been shown to substantially worsen clinical outcomes from bacterial pneumonia. Advances in our understanding of the immune response to these infections are beginning to demonstrate how these microorganisms can interact, subvert the normally effective immune response and facilitate the development of more severe and even life-threatening disease.
Publisher: American Thoracic Society
Date: 05-2015
Publisher: Wiley
Date: 12-08-2015
DOI: 10.1111/RESP.12602
Abstract: Severe or therapy-resistant asthma represents a major problem, and despite advanced treatment, many patients require oral corticosteroids (OCS). We aimed to determine if patients with severe asthma and elevated peripheral blood eosinophils (PBE) could have treatment with OCS adjusted using an algorithm that controlled PBE (<0.2 × 10(9) /L). In 11 patients, the OCS dose was adjusted to suppress PBE, leading to a reduced exacerbation frequency and improvement in asthma symptoms with an overall lower OCS dose.
Publisher: Cold Spring Harbor Laboratory
Date: 29-07-2020
DOI: 10.1101/2020.07.26.20162248
Abstract: COVID-19 is complicated by acute lung injury, and death in some in iduals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter airway epithelial cells (AECs). To determine what factors are associated with ACE2 expression particularly in patients with asthma and chronic obstructive pulmonary disease (COPD). We obtained upper and lower AECs from 145 people from two independent cohorts, aged 2-89, Newcastle (n=115), and from Perth (n= 30) Australia. The Newcastle cohort was enriched with people with asthma (n=37) and COPD (n=38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry were assessed by quantitative PCR, protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AECs. Increased gene expression of ACE2 was associated with older age (p=0.02) and male sex (p=0.03), but not pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma (p=0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in asthma (p=0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface was increased (p=0.02). ACE2 protein levels were lower in endobronchial biopsies from asthma patients. Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID-19 complications. ACE2 is the primary receptor for SARS-COV-2. We demonstrate that lower airway expression of ACE2 is increased in older adults and males. We also find that lower ACE2 expression in epithelial cells occurs in people with asthma and is associated with reduced Furin expression and increased ADAM-17 expression. This may explain at least in part the relative sparing of people with asthma from severe COVID-19 disease.
Publisher: European Respiratory Society (ERS)
Date: 12-2000
DOI: 10.1034/J.1399-3003.2000.16F13.X
Abstract: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus that may progress to bronchiectasis. The aim of the present study was to characterize airway inflammation in patients with clinically stable ABPA and asthma, and to correlate this with bronchiectasis severity. Subjects with ABPA and central bronchiectasis (ABPA-CB n=16) and ABPA with serological evidence alone (ABPA-S n=10) were studied. Comparison groups were A. fumigatus-sensitized asthma (n=19), non-A. fumigatus-sensitized asthma (n=15) and healthy controls (n=8). Hypertonic saline challenge, sputum induction and high-resolution computed tomography (HRCT) of the chest were performed. Sputum eosinophil numbers were markedly elevated in ABPA-CB (median 8.4%) compared to ABPA-S (2.4%), A. fumigatus-sensitized asthma (1.8%), asthma (1.8%) and controls (0.3%) (p<0.01) sputum eosinophil cationic protein levels were higher in ABPA-CB (median 13,706 ng.mL(-1)), compared to ABPA-S (1,633.5 ng.mL(-1)), A. fumigatus-sensitized asthma (1,550.7 ng.mL(-1)), asthma (309.2 ng.mL(-1)), and controls (110 ng.mL(-1)) (p<0.001). ABPA-CB also showed increased sputum neutrophil number (median 60.3%) compared to the other groups (controls 29.3%) (p=0.01). The severity of bronchiectasis on HRCT correlated with sputum neutrophil (r=0.6) and eosinophil number (r=0.5) but not serum immunoglobulin-E levels. In conclusion, clinically stable allergic bronchopulmonary aspergillosis with bronchiectasis is characterized by an intense heterogenous inflammatory infiltrate consisting of eosinophils and neutrophils, which correlates closely with the severity of bronchiectasis on high-resolution computed tomography. Sputum analysis may be useful in monitoring the course of allergic bronchopulmonary aspergillosis.
Publisher: American Thoracic Society
Date: 06-2011
Publisher: Wiley
Date: 11-2001
DOI: 10.1046/J.1365-2222.2001.01230.X
Abstract: Sputum induction is a safe and effective technique to study airway inflammation in stable asthma. However, it has the potential to induce bronchospasm and the safety and efficacy of the technique in acute asthma has not been determined. The objective of this study was to evaluate the safety and efficacy of a protocol to induce sputum using isotonic saline in adults with acute exacerbations of asthma. Adults (n = 47) presenting to the emergency room with acute asthma and an FEV1 > 1.0 L underwent supervised sputum induction with 0.9% saline delivered by an ultrasonic nebuliser. Induction was ceased if there was a fall of 20% or greater from baseline FEV1. Subjects had moderate to severe exacerbations of acute asthma. An adequate sputum s le was obtained in 87% of subjects. Four subjects ceased induction because of symptom distress. There was a fall > or = 20% in 28% of subjects. Bronchoconstriction was successfully reversed by salbutamol in all subjects. Predictors of significant bronchoconstriction were older age, use of ingested corticosteroids, and a requirement for high-dose nebulized salbutamol for the exacerbation. Maintenance long-acting beta2-agonist therapy protected against bronchoconstriction during sputum induction. Sputum induction in acute asthma using isotonic saline is highly efficacious in obtaining an adequate sputum s le. There is the potential for significant bronchoconstriction to occur but this can be managed safely with minimal discomfort to subjects.
Publisher: European Respiratory Society (ERS)
Date: 21-06-2023
DOI: 10.1183/13993003.00960-2021
Abstract: In people with cystic fibrosis (CF), regular nebulisation of 6% or 7% saline improves lung function however, these concentrations are not always tolerable. Clinically, some CF patients report using lower concentrations of saline to improve tolerability, yet the effects of lower concentrations are unknown. This study therefore aimed to evaluate the relative effectiveness and tolerability of 0.9% versus 3% versus 6% saline nebulised twice daily with an eFlow rapid nebuliser. This was a randomised, blinded, placebo-controlled, parallel-group, multicentre study where subjects inhaled 4 mL of 0.9%, 3% or 6% saline twice daily for 16 weeks. The primary outcome was forced expiratory volume in 1 s. The secondary outcomes were: forced vital capacity (FVC) and forced expiratory flow at 25–75% of FVC quality of life exercise capacity acquisition or loss of bacterial organisms in expectorated sputum tolerability of nebulised saline pulmonary exacerbations and adverse events. 140 participants were randomised to 0.9% (n=47), 3% (n=48) or 6% (n=45) saline. 134 participants (96%) contributed to the intention-to-treat analysis. 3% saline significantly improved lung function and increased the time to first pulmonary exacerbation compared with 0.9% saline but did not improve quality of life. 6% saline had similar benefits to 3% saline but also significantly improved quality of life compared with 3% saline. Only 6% saline delayed the time to intravenous antibiotics for pulmonary exacerbation. Tolerability and adherence were similar. Dilution of 6% saline to 3% maintains the benefits for lung function and exacerbation prevention however, the positive impacts of 6% saline on quality of life and time to i.v. antibiotics for pulmonary exacerbations are lost.
Publisher: Wiley
Date: 09-01-2018
DOI: 10.1111/RESP.13251
Abstract: Severe asthma is defined by the high treatment requirements to partly or fully control the clinical manifestations of disease. It remains a problem worldwide with a large burden for in iduals and health services. The key to improving targeted treatments, reducing disease burden and improving patient outcomes is a better understanding of the pathophysiology and mechanisms of severe disease. The heterogeneity, complexity and difficulties in undertaking clinical studies in severe asthma remain challenges to achieving better understanding and better outcomes. In this review, we focus on the structural, mechanical and inflammatory abnormalities that are relevant in severe asthma.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Elsevier BV
Date: 11-2014
Publisher: Springer Science and Business Media LLC
Date: 20-11-2019
DOI: 10.1186/S12931-019-1225-5
Abstract: Respiratory virus-induced asthma exacerbations occur frequently during pregnancy and are associated with adverse outcomes for mother and child. Primary nasal epithelial cells (pNECs) provide a useful method to study immune responses in pregnancy. pNECs were obtained by nasal brushings from pregnant and non-pregnant women with and without asthma. pNECS were infected in vitro with major group Rhinovirus 43 (RV43) and seasonal influenza (H3N2). Following infection, pNECs showed measurable quantities of interferon (IFN)-λ, IL-1β, IL-8, IP-10 and MIP1-α. pNECs provide a safe and effective method for studying respiratory epithelial cell responses during pregnancy.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.JNUTBIO.2008.06.001
Abstract: Rhinovirus infection results in increased release of inflammatory mediators from airway epithelial cells in asthma. As an antioxidant, lycopene offers protection from adverse effects of inflammation. The aim of this study was to find an appropriate method of lycopene enrichment of airway epithelial cells and to determine the effects of lycopene enrichment on the inflammatory response of cells infected by rhinovirus or exposed to lipopolysaccharide. Lycopene enrichment of airway epithelial cells using solubilisation in tetrahydrofuran versus incorporation in liposomes was compared. After determining that solubilisation of lycopene in tetrahydrofuran was the most suitable method of lycopene supplementation, airway epithelial cells (Calu-3) were incubated with lycopene (dissolved in tetrahydrofuran) for 24 h, followed by rhinovirus infection or lipopolysaccharide exposure for 48 h. The release of interleukin-6, interleukin-8 and interferon-gamma induced protein-10 (IP-10) and their messenger RNA levels were measured using enzyme linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Viral replication was measured by tissue culture infective dose of 50% assay. Lycopene concentration of cells and media were analysed using high-performance liquid chromatography. Preincubation of airway epithelial cells with lycopene (dissolved in tetrahydrofuran) delivered lycopene into the cells and resulted in a 24% reduction in interleukin-6 after rhinovirus-1B infection, 31% reduction in IP-10 after rhinovirus-43 infection and 85% reduction in rhinovirus-1B replication. Lycopene also decreased the release of IL-6 and IP-10 following exposure to lipopolysaccharide. We conclude that lycopene has a potential role in suppressing rhinovirus induced airway inflammation.
Publisher: European Respiratory Society
Date: 07-09-2020
Publisher: Wiley
Date: 30-11-2017
DOI: 10.1111/RESP.12957
Abstract: Asthma is a chronic respiratory disease characterized by respiratory symptoms, airway inflammation, airway obstruction and airway hyper-responsiveness. Asthma is common and directly affects 10% of Australians, 1-5% of adults in Asia and 300 million people worldwide. It is a heterogeneous disorder with many clinical, molecular, biological and pathophysiological phenotypes. Current management strategies successfully treat the majority of patients with asthma who have access to them. However, there is a subset of an estimated 5-10% of patients with asthma who have severe disease and are disproportionately impacted by symptoms, exacerbations and overall illness burden. The care required for this relatively small proportion of patients is also significant and has a major impact on the healthcare system. A number of new therapies that hold promise for severe asthma are currently in clinical trials or are entering the Australian and international market. However, recognition of severe asthma in clinical practice is variable, and there is little consensus on the best models of care or how to integrate emerging and often costly therapies into current practice. In this article, we report on roundtable discussions held with severe asthma experts from around Australia, and make recommendations about approaches for better patient diagnosis and assessment. We assess current models of care for patient management and discuss how approaches may be optimized to improve patient outcomes. Finally, we propose mechanisms to assess new therapies and how to best integrate these approaches into future treatment.
Publisher: Elsevier BV
Date: 07-2020
Publisher: European Respiratory Society (ERS)
Date: 09-08-2013
DOI: 10.1183/09031936.00060512
Abstract: Recent molecular-typing studies suggest cross-infection as one of the potential acquisition pathways for Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In Australia, there is only limited evidence of unrelated patients sharing indistinguishable P. aeruginosa strains. We therefore examined the point-prevalence, distribution, ersity and clinical impact of P. aeruginosa strains in Australian CF patients nationally. 983 patients attending 18 Australian CF centres provided 2887 sputum P. aeruginosa isolates for genotyping by enterobacterial repetitive intergenic consensus-PCR assays with confirmation by multilocus sequence typing. Demographic and clinical details were recorded for each participant. Overall, 610 (62%) patients harboured at least one of 38 shared genotypes. Most shared strains were in small patient clusters from a limited number of centres. However, the two predominant genotypes, AUST-01 and AUST-02, were widely dispersed, being detected in 220 (22%) and 173 (18%) patients attending 17 and 16 centres, respectively. AUST-01 was associated with significantly greater treatment requirements than unique P. aeruginosa strains. Multiple clusters of shared P. aeruginosa strains are common in Australian CF centres. At least one of the predominant and widespread genotypes is associated with increased healthcare utilisation. Longitudinal studies are now needed to determine the infection control implications of these findings.
Publisher: American Thoracic Society
Date: 14-09-2023
Publisher: European Respiratory Society
Date: 09-2017
Publisher: Wiley
Date: 2019
DOI: 10.1002/CTI2.1084
Abstract: Chronic obstructive pulmonary disease (COPD) is a progressive disease that causes significant mortality and morbidity worldwide and is primarily caused by the inhalation of cigarette smoke (CS). Lack of effective treatments for COPD means there is an urgent need to identify new therapeutic strategies for the underlying mechanisms of pathogenesis. Tristetraprolin (TTP) encoded by the Zfp36 gene is an anti‐inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD. Here, we identify a novel protective role for TTP in CS‐induced experimental COPD using Zfp36 aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNA‐destabilising factor. TTP wild‐type ( Zfp36 +/+ ) and Zfp36 aa/aa active C57BL/6J mice were exposed to CS for four days or eight weeks, and the impact on acute inflammatory responses or chronic features of COPD, respectively, was assessed. After four days of CS exposure, Zfp36 aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild‐type controls. After eight weeks, Zfp36 aa/aa mice had reduced pulmonary inflammation, airway remodelling and emphysema‐like alveolar enlargement, and lung function was improved. We then used pharmacological treatments in vivo (protein phosphatase 2A activator, AAL (S) , and the proteasome inhibitor, bortezomib) to promote the activation and stabilisation of TTP and show that hallmark features of CS‐induced experimental COPD were ameliorated. Collectively, our study provides the first evidence for the therapeutic potential of inducing TTP as a treatment for COPD.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-11-2021
DOI: 10.1126/SCITRANSLMED.AAV7223
Abstract: Inhibition of cigarette smoke–induced microRNA-21 suppresses chronic obstructive pulmonary disease through effects on a SATB1/S100A9/NF-κB axis.
Publisher: Springer Netherlands
Date: 2010
Publisher: AMPCo
Date: 07-2018
DOI: 10.5694/MJA18.00134
Abstract: Severe asthma represents a significant burden of disease, particularly in high income nations oral corticosteroids (OCS) remain an important part of the management toolkit for these patients. Corticosteroids are effective at targeting numerous elements of the type 2/eosinophilic inflammatory pathway and lead to both rapid reduction in eosinophilic inflammation and longer term reduction in airway hyper-responsiveness. Resistance or insensitivity to corticosteroids is a feature of severe asthma, with persistent type 2 inflammation often occurring despite regular use of OCS. OCS remain the only accepted, effective treatment for acute asthma, and also continue to play an important role in the long term management of severe asthma, in spite of their significant side effect profile. Even with the availability of the new biological therapies against IgE and interleukin-5, it is likely that a large proportion of patients will continue to require OCS to control their asthma. Future work should focus on optimising the balance between OCS efficacy and safety, and continued development of agents that allow reduction, or ideally discontinuation of their use, is needed.
Publisher: Wiley
Date: 17-01-2021
DOI: 10.1111/RESP.14003
Abstract: COVID‐19 is complicated by acute lung injury, and death in some in iduals. It is caused by SARS‐CoV‐2 that requires the ACE2 receptor and serine proteases to enter AEC. We determined what factors are associated with ACE2 expression particularly in patients with asthma and COPD. We obtained lower AEC from 145 people from two independent cohorts, aged 2–89 years, Newcastle ( n = 115) and Perth ( n = 30), Australia. The Newcastle cohort was enriched with people with asthma ( n = 37) and COPD ( n = 38). Gene expression for ACE2 and other genes potentially associated with SARS‐CoV‐2 cell entry was assessed by qPCR, and protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AEC. Increased gene expression of ACE2 was associated with older age ( P = 0.03) and male sex ( P = 0.03), but not with pack‐years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma patients ( P = 0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in patients with asthma ( P = 0.02), while ADAM‐17, a disintegrin that cleaves ACE2 from the surface, was increased ( P = 0.02). ACE2 protein expression was also reduced in endobronchial biopsies from asthma patients. Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over‐represented in those with COVID‐19 complications.
Publisher: American Physiological Society
Date: 2022
DOI: 10.1152/AJPLUNG.00121.2021
Abstract: Both asthma and COPD are heterogeneous diseases identified by characteristic symptoms and functional abnormalities, with airway obstruction common in both diseases. Asthma COPD overlap (ACO) does not define a single disease but is a descriptive term for clinical use that includes several overlapping clinical phenotypes of chronic airways disease with different underlying mechanisms. This literature review was initiated to describe published studies, identify gaps in knowledge, and propose future research goals regarding the disease pathology of ACO, especially the airway remodeling changes and inflammation aspects. Airway remodeling occurs in asthma and COPD, but there are differences in the structures affected and the prime anatomic site at which they occur. Reticular basement membrane thickening and cellular infiltration with eosinophils and T-helper (CD4+) lymphocytes are prominent features of asthma. Epithelial squamous metaplasia, airway wall fibrosis, emphysema, bronchoalveolar lavage (BAL) neutrophilia, and (CD8+) T-cytotoxic lymphocyte infiltrations in the airway wall are features of COPD. There is no universally accepted definition of ACO, nor are there clearly defined pathological characteristics to differentiate from asthma and COPD. Understanding etiological concepts within the purview of inflammation and airway remodeling changes in ACO would allow better management of these patients.
Publisher: American Physiological Society
Date: 12-2020
DOI: 10.1152/AJPLUNG.00374.2020
Abstract: The recurrent emergence of novel, pathogenic coronaviruses (CoVs) severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1 2002), Middle East respiratory syndrome (MERS)-CoV (2012), and most recently SARS-CoV-2 (2019) has highlighted the need for physiologically informative airway epithelial cell infection models for studying immunity to CoVs and development of antiviral therapies. To address this, we developed an in vitro infection model for two human coronaviruses alphacoronavirus 229E-CoV (229E) and betacoronavirus OC43-CoV (OC43) in differentiated primary human bronchial epithelial cells (pBECs). Primary BECs from healthy subjects were grown at air-liquid interface (ALI) and infected with 229E or OC43, and replication kinetics and time-course expression of innate immune mediators were assessed. OC43 and 229E-CoVs replicated in differentiated pBECs but displayed distinct replication kinetics: 229E replicated rapidly with viral load peaking at 24 h postinfection, while OC43 replication was slower peaking at 96 h after infection. This was associated with erse antiviral response profiles defined by increased expression of type I/III interferons and interferon-stimulated genes (ISGs) by 229E compared with no innate immune activation with OC43 infection. Understanding the host-virus interaction for previously established coronaviruses will give insight into pathogenic mechanisms underpinning SARS-CoV-2-induced respiratory disease and other future coronaviruses that may arise from zoonotic sources.
Publisher: Wiley
Date: 20-12-2014
DOI: 10.1111/CEA.12218
Abstract: Rhinoviruses (RV) are the most common acute triggers of asthma, and airway epithelial cells are the primary site of infection. Asthmatic bronchial epithelial cells (BECs) have been found to have impaired innate immune responses to RV. RV entry and replication is recognized by pathogen recognition receptors (PRRs), specifically toll-like receptor (TLR)3 and the RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Our aim was to assess the relative importance of these PRRs in primary bronchial epithelial cells (pBEC) from healthy controls and asthmatics following RV infection and determine whether deficient innate immune responses in asthmatic pBECs were due to abnormal signalling via these PRRs. The expression patterns and roles of TLR3 and MDA5 were investigated using siRNA knock-down, with subsequent RV1B infection in pBECs from each patient group. We also used BX795, a specific inhibitor of TBK1 and IKKi. Asthmatic pBECs had significantly reduced release of IL-6, CXCL-8 and IFN-λ in response to RV1B infection compared with healthy pBECs. In healthy pBECs, siMDA5, siTLR3 and BX795 all reduced release of IL-6, CXCL-10 and IFN-λ to infection. In contrast, in asthmatic pBECs where responses were already reduced, there was no further reduction in IL-6 and IFN-λ, although there was in CXCL-10. Impaired antiviral responses in asthmatic pBECs are not due to deficient expression of PRRs MDA5 and TLR3, but an inability to later activate types I and III interferon immune responses to RV infection, potentially increasing susceptibility to the effects of RV infection.
Publisher: Wiley
Date: 21-06-2013
DOI: 10.1111/RESP.12068
Abstract: Severe asthma exacerbations during pregnancy are a common complication leading to poor health outcomes for both the mother and the baby. Asthma exacerbations are caused most frequently by respiratory viruses. A balance between antiviral and inflammatory immune responses is critical during pregnancy the balance may be altered by asthma and respiratory virus infection. Peripheral blood mononuclear cells (PBMCs) were isolated from (i) non-pregnant healthy controls, (ii) pregnant non-asthmatics, (iii) post-partum non-asthmatics, (iv) non-pregnant asthmatics (v) pregnant asthmatics, and (vi) post-partum asthmatics. Cells were cultured in vitro with the mitogen phytohaemagglutinin or with a strain of the 2009 pandemic swine influenza. Interferon (IFN)-γ, interleukin (IL)-10 and IL-17 protein were measured from culture supernatant. Neutrophil counts were obtained in s les from pregnant and post-partum women. Following the phytohaemagglutinin stimulation of PBMCs, pregnant asthmatics had significantly higher IL-17 and significantly lower IFN-γ responses compared with healthy non-pregnant women. Following infection with influenza, a significant reduction was also observed in IFN-γ and IL-10 production from PBMC of pregnant asthmatics. The IL-17 response to phytohaemagglutinin correlated with the neutrophil percentage. Differences in IFN-γ, IL-10 and IL-17 were found to persist for at least 6 months post-partum. A reduction in antiviral and regulatory immunity with increased inflammation during pregnancy occurs in PBMC from pregnant women with asthma. This novel information may relate to the increased susceptibility and disease severity to respiratory virus infections observed during pregnancy.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Wiley
Date: 27-09-2018
Publisher: Wiley
Date: 15-04-2009
Publisher: John Wiley & Sons, Ltd
Date: 20-07-2005
Publisher: Elsevier BV
Date: 05-2003
Abstract: Allergic bronchopulmonary aspergillosis (ABPA) complicates chronic asthma and results from hypersensitivity to the fungus Aspergillus fumigatu s, causing an intense systemic immune response and progressive lung damage. We sought to determine whether treatment with the antifungal agent itraconazole reduced eosinophilic airway inflammation in subjects with ABPA. A randomized, double-blind, placebo-controlled trial was performed in stable subjects with ABPA (n = 29). Subjects received 400 mg of itraconazole per day (n = 15) or placebo (n = 14) for 16 weeks. All subjects were reviewed monthly with history, spirometry, and sputum induction to measure airway inflammation, serum total IgE and IgG levels to A fumigatu s, and blood eosinophil counts. By using regression analysis in a random-effects model, subjects receiving itraconazole had a decrease in sputum eosinophils of 35% per week, with no decrease seen in the placebo arm (P <.01). Sputum eosinophil cationic protein levels decreased with itraconazole treatment by 42% per week compared with 23% in the placebo group (P <.01). Itraconazole reduced systemic immune activation, leading to a decrease in serum IgE levels (310 IU/mL) compared with levels seen in the placebo group (increase of 18 IU/mL, P <.01) and a decrease in IgG levels to A fumigatu s (15.4 IU/mL) compared with levels seen in the placebo group (increase of 3.7 IU/mL, P =.03). There were fewer exacerbations requiring oral cortico-steroids in those treated with itraconazole compared with in the placebo group (P =.03). Itraconazole treatment of subjects with stable ABPA reduces eosinophilic airway inflammation, systemic immune activation, and exacerbations. These results imply that itraconazole is a potential adjunctive treatment for ABPA.
Publisher: American Thoracic Society
Date: 07-2016
Publisher: European Respiratory Society (ERS)
Date: 31-07-2012
Publisher: European Respiratory Society
Date: 07-09-2020
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2023
DOI: 10.1101/2023.06.02.23290871
Abstract: Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. However, adenoviral vectored (AdV) vaccines may be less immunogenic than mRNA vaccines against SARS-CoV-2. We assessed anti-spike and anti-vector immunity among infection-naïve Health Care Workers (HCW) following two doses of AdV (AZD1222) versus mRNA (BNT162b2) vaccine. 183 AdV and 274 mRNA vaccinees enrolled between April and October 2021. Median ages were 42 and 39 years, respectively. Blood was collected at least once, 10-48 days after vaccine dose 2. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p .001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human Adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine due to greater B cell expansion and targeting of the RBD. Pre-existing AdV vector cross-reactive antibodies were boosted following AdV vaccination but had no detectable effect on immunogenicity. mRNA SARS-CoV-2 vaccine induced higher surrogate neutralizing antibody titres than adenoviral vaccine mRNA vaccine induced a more potent, RBD-targeted B cell response than AdV vaccine Adenoviral vaccine boosted antibodies against human Adenovirus, but titres don’t correlate with anti-spike titres
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.COLSURFB.2018.08.027
Abstract: Curcumin a component of turmeric, which is derived from Curcuma longa is used as a colouring agent and as a dietary spice for centuries. Extensive studies have been done on the anti-inflammatory activity of curcumin along with its molecular mechanism involving different signalling pathways. However, the physicochemical and biological properties such as poor solubility and rapid metabolism of curcumin have led to low bioavailability and hence limits its application. Current therapies for asthma such as bronchodilators and inhaled corticosteroids (ICS) are aimed at controlling disease symptoms and prevent asthma exacerbation. However, this approach requires lifetime therapy and is associated with a constellation of side effects. This creates a clear unmet medical need and there is an urgent demand for new and more-effective treatments. The present study is aimed to formulate liposomes containing curcumin and evaluate for its anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation on BCi-NS1.1 cell line. Curcumin and salbutamol liposomes were formulated using lipid hydration method. The prepared liposomes were characterized in terms of particle size, zeta potential, encapsulation efficiency and in-vitro release profile. The liposomes were tested on BCI-NS1.1 cell line to evaluate its anti-inflammatory properties. The various pro-inflammatory markers studied were Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-1β (IL-1β) and Tumour Necrosis Factor-a (TNF-a). Additionally, molecular mechanics simulations were used to elucidate the positioning, energy minimization, and aqueous dispersion of the liposomal architecture involving lecithin and curcumin. The prepared curcumin formulation showed an average size and zeta potential of 271.3 ± 3.06 nm and -61.0 mV, respectively. The drug encapsulation efficiency of liposomal curcumin is 81.1%. Both curcumin-loaded liposomes formulation (1 μg/mL, 5 μg/mL) resulted in significant (p < 0.05) reduction in the level of pro-inflammatory marker expression such as IL-6, IL-8, IL-1β and TNF-a compared to positive control group. Liposomal curcumin with the dose of 1 μg/mL reduced the inflammatory markers more effectively compared to that of 5 μg/mL. Liposomal curcumin could be a promising intervention for asthma therapy showing their efficacy in suppressing the important pro-inflammatory markers involved in the pathogenesis of asthma.
Publisher: Informa UK Limited
Date: 07-02-2022
DOI: 10.1080/00981389.2022.2060422
Abstract: People with cystic fibrosis experience rates of anxiety and depression that are considerably higher than those of the general population. Research suggests low mental health functioning can lead to poor health outcomes and quality of life for this population. Consequently, recognition of the need for routine mental health screening and referral in cystic fibrosis care is increasing. Yet to date, less is known about the actual mental health care needs of people with cystic fibrosis. This scoping review sought to address this gap by examining the mental health care needs of adults and adolescents living with cystic fibrosis, and how are these needs are (or are not) being met. Findings suggest current efforts at mental health care provision do not adequately meet the needs of people with cystic fibrosis, highlighting the urgency of conducting high quality intervention research to support effective mental health care for this population.
Publisher: European Respiratory Society
Date: 05-09-2021
Publisher: American Thoracic Society
Date: 15-07-2014
Publisher: American Thoracic Society
Date: 05-2011
DOI: 10.1164/AJRCCM-CONFERENCE.2011.183.1_MEETINGABSTRACTS.A6198
Publisher: European Respiratory Society
Date: 04-09-2022
Publisher: Wiley
Date: 19-09-2019
DOI: 10.1111/RESP.13389
Abstract: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.
Publisher: BMJ
Date: 13-09-2012
DOI: 10.1136/THORAXJNL-2011-200708
Abstract: Acute respiratory tract infections are common ailments to all in iduals and the human rhinoviruses (HRVs) cause most of these infections. Pregnant women have increased susceptibility and disease severity to viral infections like influenza and HRVs, as do asthmatics. Successful pregnancy requires immunological modulation to permit fetal tolerance. To determine whether pregnant women have reduced innate antiviral interferon (IFN) responses to HRV infection compared with non-pregnant women. An in vitro culture system was used, where peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of 54 women, including 10 stable asthmatics who were pregnant and 10 who were not pregnant, 10 non-asthmatic women who were pregnant, 10 who were ≥6 months post partum and 10 who were not pregnant. S les were also collected from four exacerbating pregnant asthmatics. PBMCs were cultured with HRV43 and HRV1B. The antiviral proteins IFNα and IFNλ were measured from culture supernatants by ELISA. Compared with healthy non-pregnant women, pregnant women had significantly reduced innate IFN responses to HRV infection (p<0.02), persisting ≥6 months post partum (p≤0.02). Pregnant asthmatics had significantly reduced IFNλ responses compared with healthy non-pregnant women (p≤0.034), while during current asthma exacerbations a decrease in IFNα (p≤0.023) and IFNλ (p=0.007) was observed. Induction by a TLR7 agonist induced a similar pattern of decreased innate IFNs during pregnancy as observed when HRV was the inducing agent. Reduced antiviral IFNs during pregnancy and asthma provide an important mechanism for increased susceptibility, morbidity and mortality in pregnant women with respiratory viral infection.
Publisher: European Respiratory Society
Date: 04-09-2022
Publisher: Wiley
Date: 05-07-2021
DOI: 10.1111/RESP.14111
Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with none able to reverse disease or stop its progression. We explored the major molecular changes in COPD pathogenesis. We employed quantitative label‐based proteomics to map the changes in the lung tissue proteome of cigarette smoke‐induced experimental COPD that is induced over 8 weeks and progresses over 12 weeks. Quantification of 7324 proteins enabled the tracking of changes to the proteome. Alterations in protein expression profiles occurred in the induction phase, with 18 and 16 protein changes at 4‐ and 6‐week time points, compared to age‐matched controls, respectively. Strikingly, 269 proteins had altered expression after 8 weeks when the hallmark pathological features of human COPD emerge, but this dropped to 27 changes at 12 weeks with disease progression. Differentially expressed proteins were validated using other mouse and human COPD bronchial biopsy s les. Major changes in RNA biosynthesis (heterogeneous nuclear ribonucleoproteins C1/C2 [HNRNPC] and RNA‐binding protein Musashi homologue 2 [MSI2]) and modulators of inflammatory responses (S100A1) were notable. Mitochondrial dysfunction and changes in oxidative stress proteins also occurred. We provide a detailed proteomic profile, identifying proteins associated with the pathogenesis and disease progression of COPD establishing a platform to develop effective new treatment strategies.
Publisher: Informa UK Limited
Date: 18-07-2023
DOI: 10.1080/02770903.2022.2093217
Abstract: In Australia, the regional prevalence of difficult-to-treat asthma is unknown. We aimed to describe regional variation in difficult-to-treat asthma prevalence and oral corticosteroid (OCS) use. In this retrospective, observational, longitudinal study using data from March 2018-February 2019 in the NostraData longitudinal database, prescriptions dispensed for obstructive airway disease were processed through a high-level algorithm to identify patients with asthma. Difficult-to-treat asthma was defined by ≥2 high-dosage inhaled corticosteroids plus long-acting beta-agonist prescriptions over 6 months. Patients who additionally received OCS prescriptions sufficient to treat ≥2 exacerbations over 6 months were classified as having uncontrolled difficult-to-treat asthma. Patient-level data were analyzed across 340 geographic areas in Australia to determine regional prevalence of difficult-to-treat asthma, uncontrolled difficult-to-treat asthma, and OCS use. Of 1 851 129 people defined as having asthma, 440 800 (24%) were classified as having difficult-to-treat disease. Of those difficult-to-treat asthma patients, 96 338 (22%) were considered to have uncontrolled disease. Between 29% and 48% of patients had difficult-to-treat asthma in 49 geographic areas, most frequently located in Western Australia. Between 26% and 67% of patients had uncontrolled difficult-to-treat asthma in 29 geographic areas (mostly in Eastern Australia). Overall, a wide variability of asthma severity and control was observed among regions. Despite global and national guidelines, regional differences in the prevalence of difficult-to-treat asthma and uncontrolled difficult-to-treat asthma and OCS use exist in Australia. Understanding these regional variations should inform policy and target management in the areas with the greatest unmet need.
Publisher: European Respiratory Society (ERS)
Date: 15-09-2012
DOI: 10.1183/09031936.00022011
Abstract: The receptor for advanced glycation end-products (RAGE) is a pattern-recognition receptor involved in the host response to injury, infection and inflammation. It is a membrane receptor, but also has soluble forms (sRAGE). Deficiencies in sRAGE are linked to heightened inflammation in various chronic conditions. We determined whether airway and systemic levels of sRAGE and the RAGE ligands HMGB1 (high-mobility group box-1) and serum amyloid A (SAA) are related to neutrophilic inflammation in asthma and chronic obstructive pulmonary disease (COPD). Bronchial lavage fluid from subjects with moderate-to-severe persistent asthma (n = 16) or COPD (n = 37), or from healthy controls (n = 18), was analysed for neutrophils, total sRAGE, endogenous secretory RAGE (esRAGE), HMGB1 and SAA. We also determined systemic levels of sRAGE in a separate group of asthmatic (n = 101) and COPD (n = 34) subjects. Subjects with neutrophilic asthma or COPD had undetectable levels of lung sRAGE, while levels of sRAGE in asthma/COPD without neutrophilia were similar to those in controls. Systemic sRAGE was significantly decreased in subjects with neutrophilic asthma or COPD compared with those without airway neutrophilia. There was significant positive correlation between total sRAGE and esRAGE in the lung and systemically. HMGB1 levels were similar in all subject groups, while SAA was below detectable levels. Neutrophilic airway inflammation in asthma and COPD is associated with reduced sRAGE.
Publisher: Public Library of Science (PLoS)
Date: 07-03-2012
Publisher: Wiley
Date: 05-2021
Publisher: Elsevier BV
Date: 08-2015
Publisher: Wiley
Date: 11-2017
Publisher: Wiley
Date: 05-02-2023
DOI: 10.1111/CODI.16472
Abstract: Cystic fibrosis (CF) is a hereditary, life‐limiting, multi‐system condition that results in chronic respiratory infections, pancreatic insufficiency and intestinal inflammation. Evidence indicates that CF patients develop colorectal cancer (CRC) earlier and more often than the general population. Intestinal dysbiosis resulting from genetics and CF treatment is a contributing factor. This systematic review aims to evaluate the literature to compare the microbiome of adult CF patients to non‐CF patients and to assess if these changes correspond with known CRC microbiome alterations. A systematic review across five databases was performed according to PRISMA guidelines. Studies focusing on adult CF patients using next generation sequencing and with appropriate non‐CF controls were included. Two reviewers independently screened results and assessed study quality using the Newcastle–Ottawa scale. The search generated 2757 results. 118 studies were retained after reviewing the title/abstract and full article review found five studies met the inclusion criteria. All studies consistently showed reduced microbial ersity in CF patients and unique clustering between CF and control cohorts. Thirty‐four genera and 27 species were differently expressed between CF and controls. The CF cohort had a reduced number of short‐chain fatty acid (SCFA) producing bacteria and a higher abundance of bacteria associated with CRC compared to controls. There was substantial heterogeneity across all the studies with regard to methodologies and reporting. However, all studies consistently found CF patients had reduced microbial ersity, fewer SCFA producing bacteria and increased CRC‐associated bacteria. Further prospective studies employing consistent multi‐omics approaches are needed to improve our understanding of the CF gut microbiome and its involvement in early onset CRC. This is the first systematic review to assess adult CF colorectal microbiome changes. This study shows CF patients have reduced SCFA producing bacteria and increased CRC‐associated bacteria compared to non‐CF patients and may help to explain the increased risk of CRC in the CF cohort.
Publisher: eLife Sciences Publications, Ltd
Date: 14-02-2017
DOI: 10.7554/ELIFE.20444
Abstract: Influenza virus infections have a significant impact on global human health. In iduals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.
Publisher: American Thoracic Society
Date: 21-08-2023
A Sputum 6 Gene Expression Signature Predicts Inflammatory Phenotypes and Future Exacerbations of COPD
Publisher: Informa UK Limited
Date: 07-2020
DOI: 10.2147/COPD.S245519
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.RMED.2010.04.003
Abstract: Asthma guidelines recommend reducing inhaled corticosteroids (ICS) to the minimum effective dose, but the timing of long-acting beta(2)-agonist (LABA) withdrawal is unclear. Recent FDA guidelines recommend LABA withdrawal once asthma is well-controlled. This 13-month double-blind study of patients taking high-dose combination therapy investigated the effect of discontinuation of LABA before ICS down-titration. Adults using salmeterol/fluticasone combination (SFC) 50/500 microg bd were randomized to SFC 50/500 microg bd or fluticasone propionate (FP) 500 microg bd, with subsequent ICS down-titration 8-weekly using a clinical algorithm. The primary outcome was mean daily FP dose, including ICS for exacerbations. 82 subjects were randomized. Asthma was well-controlled at baseline, with mean FEV(1) 84.8% predicted and Asthma Control Questionnaire (ACQ) score 0.9. There was no significant difference in mean daily FP dose (SFC: 721 microg, FP:816 microg, p = 0.3), but final dose was lower with SFC (534 microg cf. 724 microg, p = 0.005). ICS dose was reduced by >or=80% in 41% SFC and 15% FP patients. Ambulatory lung function was significantly higher with SFC, but there were no differences between groups in rescue beta(2)-agonist use, clinic spirometry, airway responsiveness, ACQ, sputum eosinophils or FeNO. Baseline airway responsiveness, and pre-reduction blood eosinophils, were significant predictors of mean daily FP dose and dose reduction failure respectively. Many patients prescribed high-dose combination therapy may be over-treated. Substantial reductions in dose can be achieved with a clinical algorithm, reaching lower FP doses with SFC than FP without losing asthma control or increasing disease activity. This study was commenced before mandatory registration of clinical trials.
Publisher: European Respiratory Society (ERS)
Date: 16-02-2021
DOI: 10.1183/16000617.0185-2019
Abstract: Pathological features of both asthma and COPD coexist in some patients and this is termed asthma-COPD overlap (ACO). ACO is heterogeneous and patients exhibit various combinations of asthma and COPD features, making it difficult to characterise the underlying pathogenic mechanisms. There are no controlled studies that define effective therapies for ACO, which arises from the lack of international consensus on the definition and diagnostic criteria for ACO, as well as scant in vitro and in vivo data. There remain unmet needs for experimental models of ACO that accurately recapitulate the hallmark features of ACO in patients. The development and interrogation of such models will identify underlying disease-causing mechanisms, as well as enabling the identification of novel therapeutic targets and providing a platform for assessing new ACO therapies. Here, we review the current understanding of the clinical features of ACO and highlight the approaches that are best suited for developing representative experimental models of ACO.
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Wiley
Date: 07-06-2022
DOI: 10.1111/RESP.14302
Abstract: Severe asthma (SA) is a heterogeneous disease. Transcriptomic analysis contributes to the understanding of pathogenesis necessary for developing new therapies. We sought to identify and validate mechanistic pathways of SA across two independent cohorts. Transcriptomic profiles from U‐BIOPRED and Australian NOVocastrian Asthma cohorts were examined and grouped into SA, mild/moderate asthma (MMA) and healthy controls (HCs). Differentially expressed genes (DEGs), canonical pathways and gene sets were identified as central to SA mechanisms if they were significant across both cohorts in either endobronchial biopsies or induced sputum. Thirty‐six DEGs and four pathways were shared across cohorts linking to tissue remodelling/repair in biopsies of SA patients, including SUMOylation, NRF2 pathway and oxidative stress pathways. MMA presented a similar profile to HCs. Induced sputum demonstrated IL18R1 as a shared DEG in SA compared with healthy subjects. We identified enrichment of gene sets related to corticosteroid treatment immune‐related mechanisms activation of CD4 + T cells, mast cells and IL18R1 and airway remodelling in SA. Our results identified differentially expressed pathways that highlight the role of CD4 + T cells, mast cells and pathways linked to ongoing airway remodelling, such as IL18R1, SUMOylation and NRF2 pathways, as likely active mechanisms in the pathogenesis of SA.
Publisher: Elsevier BV
Date: 05-2020
DOI: 10.1016/J.JCF.2019.12.006
Abstract: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events. Data was collected from 7 Australian CF centres on 105 patients 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI 0.306 - 0.676), p < 0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%. Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent, and resulted in a very high discontinuation rate.
Publisher: Informa UK Limited
Date: 03-05-2016
Publisher: Springer Science and Business Media LLC
Date: 22-09-2016
Publisher: Wiley
Date: 27-04-2018
DOI: 10.1002/RCR2.325
Publisher: Informa UK Limited
Date: 05-2016
DOI: 10.2147/COPD.S103607
Publisher: Cold Spring Harbor Laboratory
Date: 19-10-2023
Publisher: Public Library of Science (PLoS)
Date: 09-2017
Publisher: Frontiers Media SA
Date: 06-02-2018
Publisher: European Respiratory Society
Date: 07-09-2020
Publisher: Springer Science and Business Media LLC
Date: 20-01-2013
DOI: 10.1038/NM.3049
Abstract: Allergic airway inflammation is associated with activation of innate immune pathways by allergens. Acute exacerbations of asthma are commonly associated with rhinovirus infection. Here we show that, after exposure to house dust mite (HDM) or rhinovirus infection, the E3 ubiquitin ligase midline 1 (MID1) is upregulated in mouse bronchial epithelium. HDM regulates MID1 expression in a Toll-like receptor 4 (TLR4)- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. MID1 decreases protein phosphatase 2A (PP2A) activity through association with its catalytic subunit PP2Ac. siRNA-mediated knockdown of MID1 or pharmacological activation of PP2A using a nonphosphorylatable FTY720 analog in mice exposed to HDM reduces airway hyperreactivity and inflammation, including the expression of interleukin-25 (IL-25), IL-33 and CCL20, IL-5 and IL-13 release, nuclear factor (NF)κB activity, p38 mitogen-activated protein kinase (MAPK) phosphorylation, accumulation of eosinophils, T lymphocytes and myeloid dendritic cells, and the number of mucus-producing cells. MID1 inhibition also limited rhinovirus-induced exacerbation of allergic airway disease. We found that MID1 was upregulated in primary human bronchial epithelial cells upon HDM or rhinovirus exposure, and this correlated with TRAIL and CCL20 expression. Together, these findings identify a key role of MID1 in allergic airway inflammation and links innate immune pathway activation to the development and exacerbation of asthma.
Publisher: European Respiratory Society (ERS)
Date: 07-03-2019
DOI: 10.1183/13993003.02058-2018
Abstract: “Treatable traits” have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each in idual to improve outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.
Publisher: Informa UK Limited
Date: 07-2016
DOI: 10.2147/COPD.S100338
Publisher: Proceedings of the National Academy of Sciences
Date: 03-01-2012
Abstract: Chronic obstructive pulmonary disease (COPD) will soon be the third most common cause of death globally. Despite smoking cessation, neutrophilic mucosal inflammation persistently damages the airways and fails to protect from recurrent infections. This maladaptive and excess inflammation is also refractory to glucocorticosteroids (GC). Here, we identify serum amyloid A (SAA) as a candidate mediator of GC refractory inflammation in COPD. Extrahepatic SAA was detected locally in COPD bronchoalveolar lavage fluid, which correlated with IL-8 and neutrophil elastase, consistent with neutrophil recruitment and activation. Immunohistochemistry detected SAA was in close proximity to airway epithelium, and in vitro SAA triggered release of IL-8 and other proinflammatory mediators by airway epithelial cells in an ALX/FPR2 (formyl peptide receptor 2) receptor-dependent manner. Lipoxin A 4 (LXA 4 ) can also interact with ALX/FPR2 receptors and lead to allosteric inhibition of SAA-initiated epithelial responses (pA 2 13 nM). During acute exacerbation, peripheral blood SAA levels increased dramatically and were disproportionately increased relative to LXA 4 . Human lung macrophages (CD68 + ) colocalized with SAA and GCs markedly increased SAA in vitro (THP-1, pEC 50 43 nM). To determine its direct actions, SAA was administered into murine lung, leading to induction of CXC chemokine ligand 1/2 and a neutrophilic response that was inhibited by 15-epi-LXA 4 but not dexamethasone. Taken together, these findings identify SAA as a therapeutic target for inhibition and implicate SAA as a mediator of GC-resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors.
Publisher: Wiley
Date: 09-2016
DOI: 10.1111/IMJ.13166
Abstract: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway however, effectiveness data in a population with significant comorbidities are limited. To describe severe allergic asthma, omalizumab treatment outcomes and predictors of response among the Australian Xolair Registry participants. A web-based post-marketing surveillance registry was established to characterise the use, effectiveness and adverse effects of omalizumab (Xolair) for severe allergic asthma. Participants (n = 192) (mean age 51 years, 118 female) with severe allergic asthma from 21 clinics in Australia were assessed, and 180 received omalizumab therapy. They had poor asthma control (Asthma Control Questionnaire, ACQ-5, mean score 3.56) and significant quality of life impairment (Asthma-related Quality of Life Questionnaire score 3.57), and 52% were using daily oral corticosteroid (OCS). Overall, 95% had one or more comorbidities (rhinitis 48%, obesity 45%, cardiovascular disease 23%). The omalizumab responder rate, assessed by an improvement of at least 0.5 in ACQ-5, was high at 83%. OCS use was significantly reduced. The response in participants with comorbid obesity and cardiovascular disease was similar to those without these conditions. Baseline ACQ-5 ≥ 2.0 (P = 0.002) and older age (P = 0.05) predicted the magnitude of change in ACQ-5 in response to omalizumab. Drug-related adverse events included anaphylactoid reactions (n = 4), headache (n = 2) and chest pains (n = 1). Australian patients with severe allergic asthma report a high disease burden and have extensive comorbidity. Symptomatic response to omalizumab was high despite significant comorbid disease. Omalizumab is an effective targeted therapy for severe allergic asthma with comorbidity in a real-life setting.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.RMED.2011.10.007
Abstract: Post infectious chronic cough is a disabling illness. In 2009 an influenza pandemic occurred due to a novel strain of H1N1 influenza. Prolonged symptoms such as chronic cough remaining after the infection has cleared have not been examined. This study sought to investigate the prevalence, characteristics and mechanism of chronic cough following laboratory-confirmed H1N1 2009 influenza. Out of 836 eligible patients who had been tested by PCR assay for H1N1, 136 responders participated. Nineteen underwent detailed clinical investigation of cough, and airway function using symptom questionnaires, hypertonic saline challenge, and cough monitoring. Post H1N1 chronic cough was reported by 43%, and chronic cough after non-H1N1 infection was present in 36% of participants. In the participants who progressed to testing objectively measured cough frequency was 3 times greater there was a 9-fold increase in cough reflex sensitivity and greater quality of life impairment in the participants with postinfectious chronic cough following H1N1 infection than for the participants with no cough following H1N1 infection and for the healthy controls. This study reports the first evaluation of chronic cough following H1N1 infection. Patients that develop chronic cough after H1N1 infection display increased cough reflex sensitivity up to 220 days after confirmed infection. There is an absence of associated risk factors and less impairment in quality of life compared to those patients normally seen in a specialist cough clinic. The associated mechanism was found to be cough reflex hypersensitivity. This clinical trial has been registered with the Australian New Zealand Clinical Trials Register, ACTRN12610000540011.
Publisher: American Physiological Society
Date: 2021
DOI: 10.1152/AJPLUNG.00437.2020
Abstract: Lungs of smokers and chronic obstructive pulmonary disease (COPD) are severely compromised and are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attack. The dangerous combination of enhanced SARS-CoV-2 attachment receptor protein ACE2 along with an increase in endocytic vacuoles will enable viral attachment, entry, and replication. The objective of the study was to identify the presence of SARS-CoV-2 host attachment receptor angiotensin-converting enzyme-2 (ACE2) along with endocytic vacuoles, early endosome antigen-1 (EEA1), late endosome marker RAB7, cathepsin-L, and lysosomal associated membrane protein-1 (LAMP-1) as lysosome markers in the airways of smokers and COPD patients. The study design was cross-sectional and involved lung resections from 39 patients in total, which included 19 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I or GOLD stage II COPD, of which 9 were current smokers with COPD (COPD-CS) and 10 were ex-smokers with COPD (COPD-ES), 10 were normal lung function smokers, and 10 were never-smoking normal controls. Immunostaining for ACE2, EEA1, RAB7, and cathepsin-L was done. A comparative description for ACE2, EEA1, RAB7, and cathepsin-L expression pattern is provided for the patient groups. Furthermore, staining intensity for LAMP-1 lysosomes was measured as the ratio of the LAMP-1-stained areas per total area of epithelium or subepithelium, using Image ProPlus v7.0 software. LAMP-1 expression showed a positive correlation to patient smoking history while in COPD LAMP-1 negatively correlated to lung function. The active presence of ACE2 protein along with endocytic vacuoles such as early/late endosomes and lysosomes in the small airways of smokers and COPD patients provides evidence that these patient groups could be more susceptible to COVID-19.
Publisher: Oxford University Press (OUP)
Date: 12-06-2012
Abstract: Pregnant women are considered to have a high risk for influenza virus infection, although little is known about the biological reasons for this risk. Antiviral immunity is critical during influenza virus infection, and understanding the changes that occur during pregnancy and the effect of vaccination is essential for improving health outcomes for mother and baby. Peripheral blood mononuclear cells (PBMCs) were isolated from 26 healthy, nonpregnant women and 28 healthy pregnant women and cultured with 2009 pandemic influenza A virus subtype H1N1 (H1N1/09). Protein concentrations of interferon α (IFN-α), IFN-λ, and IFN-γ were measured from culture supernatant. Messenger RNA expression of protein kinase R (PKR) and Toll-like receptors 3, 7, and 9 was also measured from cell lysates. PBMCs from pregnant women produced significantly less IFN-α (median level, 114.06 pg/mL [range, 51.48-394.9]) and IFN-λ (median level, 30.65 pg/mL [range, 0-260]), compared with PBMCs from nonpregnant women (median level, 800.38 pg/mL [range, 259-1458] and 479.87 pg/mL [257.1-1113], respectively P < .01). PKR expression was also significantly reduced in PBMCs from pregnant women (P < .05). Vaccination significantly improved innate and adaptive immunity in pregnancy (P < .01). PBMCs from nonvaccinated pregnant women have attenuated antiviral immunity following H1N1/09 stimulation, but vaccination improves this response. These novel findings help improve understanding of the increased susceptibility and disease severity to influenza virus infection during pregnancy and the importance of influenza vaccination.
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2023
DOI: 10.1101/2023.06.04.23290702
Abstract: Chronic obstructive pulmonary disease (COPD) is a complex disorder with a high degree of interin idual variability. Gastrointestinal dysfunction is common in COPD patients and has been proposed to influence the clinical progression of the disease. Using the presence of bile acid(s) (BA) in bronchoalveolar lavage fluid (BAL) as a marker of gastric aspiration, we evaluated the relationships between BAs, clinical outcomes, and bacterial lung colonisation. We used BAL specimens from a cohort of COPD patients and healthy controls. Bile acids were profiled and quantified in BAL supernatants using mass spectrometry. Microbial DNA was extracted from BAL cell pellets and quantified using qPCR. We profiled the BAL microbiota using an licon sequencing approach targeting the V3-V4 region of the 16S rRNA gene. Detection of BAs in BAL was more likely at earliest clinical stages of COPD and was independent of the degree of airway obstruction. BAL specimens with BAs demonstrated higher bacterial biomass and lower ersity. Likewise, the odds of recovering bacterial cultures from BAL were higher if BAs were also detected. Detection of BAs in BAL was not associated with either inflammatory markers or clinical outcomes. We also observed different bacterial community types in BAL, which were associated with different clinical groups, levels of inflammatory markers, and the degree of airway obstruction. Detection of BAs in BAL was associated with different parameters of airway ecology. Further studies are needed to evaluate whether BAs in BAL can be used to stratify patients and for predicting disease progression trajectories.
Publisher: American Society for Microbiology
Date: 05-2009
DOI: 10.1128/JCM.00014-09
Abstract: Pseudomonas aeruginosa is an important cause of pulmonary infection in cystic fibrosis (CF). Its correct identification ensures effective patient management and infection control strategies. However, little is known about how often CF sputum isolates are falsely identified as P. aeruginosa . We used P. aeruginosa -specific duplex real-time PCR assays to determine if 2,267 P. aeruginosa sputum isolates from 561 CF patients were correctly identified by 17 Australian clinical microbiology laboratories. Misidentified isolates underwent further phenotypic tests, lified rRNA gene restriction analysis, and partial 16S rRNA gene sequence analysis. Participating laboratories were surveyed on how they identified P. aeruginosa from CF sputum. Overall, 2,214 (97.7%) isolates from 531 (94.7%) CF patients were correctly identified as P. aeruginosa . Further testing with the API 20NE kit correctly identified only 34 (59%) of the misidentified isolates. Twelve (40%) patients had previously grown the misidentified species in their sputum. Achromobacter xylosoxidans ( n = 21), Stenotrophomonas maltophilia ( n = 15), and Inquilinus limosus ( n = 4) were the species most commonly misidentified as P. aeruginosa . Overall, there were very low rates of P. aeruginosa misidentification among isolates from a broad cross section of Australian CF patients. Additional improvements are possible by undertaking a culture history review, noting colonial morphology, and performing stringent oxidase, DNase, and colistin susceptibility testing for all presumptive P. aeruginosa isolates. Isolates exhibiting atypical phenotypic features should be evaluated further by additional phenotypic or genotypic identification techniques.
Publisher: Wiley
Date: 03-2000
DOI: 10.1046/J.1440-1843.2000.00226.X
Abstract: To evaluate induced sputum eosinophils in asthma and chronic cough. This was an analytical, cross-sectional study set in an ambulatory respiratory clinic. Subjects (n=75) referred for evaluation of symptomatic asthma or episodic respiratory symptoms had a clinical assessment, spirometry, hypertonic saline challenge and induced sputum. Two diagnostic groups were identified. The first group comprised subjects with symptomatic asthma and variable airway obstruction (VAO) (n=32). The second group included subjects with episodic respiratory symptoms and no VAO (n=43). The prevalence of eosinophilic bronchitis (eosinophils >2.75%) was greatest in asthma (n=14, 44%), compared to the episodic respiratory symptoms group (n=9, 21%, P = 0.02). Clinical variables did not predict increased eosinophils (P > 0.05). Sputum eosinophils were highest in asthmatics not using inhaled corticosteroids (6.5% vs 0.5%, P = 0.02). Sputum neutrophils were higher in subjects using inhaled corticosteroid (53% vs 25%, P = 0.04). Airway inflammation with eosinophilia was common among patients presenting to a respiratory clinic, especially those with asthma who were not using inhaled corticosteroids. Induced sputum also identified eosinophilic bronchitis in those without asthma. It was not possible to detect the presence or absence of airway eosinophilia by routine clinical assessment. The results in this study imply that the assessment of induced sputum eosinophils may be a useful guide to therapy, especially in the assessment of persistent symptoms in asthmatics on corticosteroids, and in the assessment of non-asthmatic subjects with symptoms.
Blood Neutrophils In COPD But Not Asthma Exhibit A Primed Phenotype With Downregulated CD62L Expression
Publisher: Informa UK Limited
Date: 11-2019
DOI: 10.2147/COPD.S222486
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1093/AJCN/NQY082
Abstract: Inflammation is associated with an increased risk of a range of chronic diseases. A diet high in fruit and vegetables may help to reduce inflammation, as fruit and vegetables are rich sources of antioxidants and other biologically active substances, which may improve immune function. To summarize the evidence, we executed a systematic review and meta-analysis examining the effects of fruit and/or vegetable intake on inflammatory biomarkers and immune cells in humans with different diseases and conditions. Electronic databases including PubMed, Cochrane, CINAHL, and EMBASE were systematically searched up to March 2018. Eighty-three studies were included. Of these, 71 (86%) were clinical trials, and 12 were observational studies (n = 10 cross-sectional and n = 2 cohort). Amongst the observational research, n = 10 studies found an inverse association between intakes of fruit or vegetables and inflammatory biomarkers. Similarly, the majority of the intervention studies (68%, n = 48) reported beneficial effects of fruit or vegetable intake on ≥1 biomarker of systemic or airway inflammation. A meta-analysis of included studies showed that fruit or vegetable intake decreased circulating levels of C-reactive protein and tumor necrosis factor-α (P < 0.05) and increased the γδ-T cell population (P < 0.05). In conclusion, this review suggests that higher intakes of fruit and vegetables lead to both a reduction in proinflammatory mediators and an enhanced immune cell profile.
Publisher: American Thoracic Society
Date: 2017
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.VACCINE.2011.07.087
Abstract: We aimed to estimate the effectiveness of H1N1/09 containing influenza vaccines against hospitalization from influenza in Australia. We performed a test-negative case control study in patients hospitalized in 15 sentinel Australian hospitals between March and November 2010, comparing influenza vaccination (H1N1/09 monovalent or 2010 seasonal trivalent) in hospitalized patients with PCR-confirmed influenza compared to PCR-negative controls. Between March and November 2010, 1169 hospitalized patients were tested for suspected influenza, of which influenza vaccine status was ascertained in 165/238 patients with H1N1/09 influenza, 40/64 with seasonal influenza and 558/867 test negative controls 24% of H1N1/09 cases, 43% of seasonal influenza cases and 54% of controls were vaccinated. VE against hospitalisation with H1N1/09 influenza after adjusting for age, medical comorbidities and pregnancy status was estimated at 49% (95% CI: 13%, 70%). Influenza vaccination was associated with a reduction in hospitalisation caused by H1N1/09 influenza in the 2010 southern hemisphere winter season.
Publisher: Oxford University Press (OUP)
Date: 20-10-2017
Publisher: Wiley
Date: 22-11-2007
Publisher: American Society for Clinical Investigation
Date: 06-04-2017
Publisher: European Respiratory Society (ERS)
Date: 10-2019
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/407271
Abstract: Background . Innate immune antimicrobial peptides, including β -defensin-1, promote the chemotaxis and activation of several immune cells. The role of β -defensin-1 in asthma and chronic obstructive pulmonary disease (COPD) remains unclear. Methods . Induced sputum was collected from healthy controls and in iduals with asthma or COPD. β -defensin-1 protein in sputum supernatant was quantified by ELISA. Biomarker potential was examined using receiver operating characteristic curves. β -defensin-1 release from primary bronchial epithelial cells (pBECs) was investigated in culture with and without cigarette smoke extract (CSE). Results . Airway β -defensin-1 protein was elevated in COPD participants compared to asthma participants and healthy controls. Inflammatory phenotype had no effect on β -defensin-1 levels in asthma or COPD. β -defensin-1 protein was significantly higher in severe asthma compared to controlled and uncontrolled asthma. β -defensin-1 protein could predict the presence of COPD from both healthy controls and asthma patients. Exposure of pBECs to CSE decreased β -defensin-1 production in healthy controls however in pBECs from COPD participants the level of β -defensin-1 remanied unchanged. Conclusions . Elevated β -defensin-1 protein is a feature of COPD and severe asthma regardless of inflammatory phenotype. β -defensin-1 production is dysregulated in the epithelium of patients with COPD and may be an effective biomarker and potential therapeutic target.
Publisher: Routledge
Date: 20-05-2018
Publisher: Wiley
Date: 24-09-2020
DOI: 10.1002/RCR2.670
Publisher: F1000 Research Ltd
Date: 23-08-2016
DOI: 10.12688/F1000RESEARCH.9236.1
Abstract: This review highlights the important articles published in the area of asthma research from January 2015 to July 2016. In basic science, significant advances have been made in understanding the link between the innate immune response and type II acquired immune responses in asthma and the role of the airway epithelium. Novel information continues to emerge with regard to the pathogenesis and heterogeneity of severe asthma. There have been important translational clinical trials in the areas of childhood asthma, treatment of allergy to improve asthma outcomes, and improving drug delivery to optimize the management of asthma. In addition, there are increasing data concerning the application of biological agents to the management of severe asthma. This body of work discusses the most notable advances in the understanding and management of asthma.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Wiley
Date: 06-2019
DOI: 10.1111/IMJ.14158
Abstract: The inter-jurisdictional National Mutual Acceptance (NMA) scheme for Human Research Ethics Committee (HREC) approvals of human research is designed to reduce the reported delays and costs of ethical review. Introduction of the NMA set forth an uncoupling of the ethics and governance review processes, permitting a single ethical review for multiple sites, while continuing separate governance review for each centre covering financial and operational aspects of the research project. To compare the time required to gain ethics and governance approvals in Australia for a non-interventional investigator-led study from December 2015 to approval times for an earlier pre-NMA study utilising a similar study design and study sites and evaluate the effect that the NMA has had on total approval time for non-interventional multi-centre projects. We recorded the time taken to obtain ethics and governance approval at 16 sites for our nationwide low-risk non-interventional study looking at the prevalence and aetiology of non-tuberculous mycobacterial infection in people with cystic fibrosis in Australia. Applications were submitted to three hospitals and one university HREC to conduct our study at 16 hospital sites, HREC approval took from 16 to 79 days (median 28). Subsequent site-specific governance approval at 15 hospital sites took 23-225 days (median 83). The entire process of gaining ethical and governance approval to conduct the study at 16 sites took 24 months at an estimated cost of AU$56000 (US$ 42 000). Lengthy governance approval processes negate benefits gained from centralised ethics review under the NMA.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Frontiers Media SA
Date: 2012
Publisher: Wiley
Date: 05-01-2020
DOI: 10.1002/IID3.282
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1038/S41385-019-0163-3
Abstract: Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patients. In animal models of colitis, pulmonary inflammation is driven by neutrophilic infiltrations, primarily in response to the systemic bacteraemia and increased bacterial load in the lungs. Platelet activating factor receptor (PAFR) plays a critical role in regulating pulmonary responses to infection in conditions, such as chronic obstructive pulmonary disease and asthma. We investigated the role of PAFR in pulmonary EIMs of IBD, using dextran sulfate sodium (DSS) and anti-CD40 murine models of colitis. Both models induced neutrophilic inflammation, with increased TNF and IL-1β levels, bacterial load and PAFR protein expression in mouse lungs. Antagonism of PAFR decreased lung neutrophilia, TNF, and IL-1β in an NLRP3 inflammasome-dependent manner. Lipopolysaccharide from phosphorylcholine (ChoP)-positive bacteria induced NLRP3 and caspase-1 proteins in human alveolar epithelial cells, however antagonism of PAFR prevented NLRP3 activation by ChoP. Amoxicillin reduced bacterial populations in the lungs and reduced NLRP3 inflammasome protein levels, but did not reduce PAFR. These data suggest a role for PAFR in microbial pattern recognition and NLRP3 inflammasome signaling in the lung.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2010
DOI: 10.1007/S00011-009-0102-Y
Abstract: Pregnancy can influence the course of maternal asthma, but the mechanisms are presently unknown. The aim of the present study was to access maternal immune cell profiles in the presence and absence of asthma and to determine the effect of pregnancy-derived factors on epithelial cell function. Cells from the human bronchial epithelial cell line BEAS-2B were treated with plasma from pregnant or nonpregnant asthmatic and nonasthmatic subjects. Cell culture supernatants were collected after 24 h and assayed for IL-6, IL-8, eotaxin, RANTES and sICAM-1 protein using ELISA. Maternal immune cell count and peripheral blood chemotactic response to plasma from pregnant and non-pregnant asthmatic subjects were also assessed. The presence of maternal asthma during pregnancy was associated with increased monocyte and neutrophil numbers, increased BEAS-2B cell production of IL-8 and sICAM-1 (P < 0.05) and increased chemotactic capacity relative to pregnant women without asthma. The results of this study suggest that circulating pregnancy-related factors enhance chemotactic mediators in epithelial cells in the presence of asthma. This may be one mechanism that contributes to pregnancy-induced changes in asthma.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2022
DOI: 10.1038/S41598-022-10801-Z
Abstract: Gestational diabetes mellitus (GDM) plus rectus abdominis muscle (RAM) myopathy predicts long-term urinary incontinence (UI). Atrophic and stiff RAM are characteristics of diabetes-induced myopathy (DiM) in pregnant rats. This study aimed to determine whether swimming exercise (SE) has a therapeutic effect in mild hyperglycemic pregnant rats model. We hypothesized that SE training might help to reverse RAM DiM. Mild hyperglycemic pregnant rats model was obtained by a unique subcutaneous injection of 100 mg/kg streptozotocin (diabetic group) or citrate buffer (non-diabetic group) on the first day of life in Wistar female newborns. At 90 days of life, the rats are mated and randomly allocated to remain sedentary or subjected to a SE protocol. The SE protocol started at gestational day 0 and consisted of 60 min/day for 6 days/week in a period of 20 days in a swim tunnel. On day 21, rats were sacrificed, and RAM was collected and studied by picrosirius red, immunohistochemistry, and transmission electron microscopy. The SE protocol increased the fiber area and diameter, and the slow-twitch and fast-twitch fiber area and diameter in the diabetic exercised group, a finding was also seen in control sedentary animals. There was a decreased type I collagen but not type III collagen area and showed a similar type I/type III ratio compared with the control sedentary group. In conclusion, SE during pregnancy reversed the RAM DiM in pregnant rats. These findings may be a potential protocol to consider in patients with RAM damage caused by GDM.
Publisher: Wiley
Date: 04-2015
DOI: 10.1111/RESP.12381
Abstract: Exposure to airborne particulate matter (PM) may promote development of childhood asthma and trigger acute exacerbations of existing asthma via injury to airway epithelial cells (AEC). We compared the response of AEC to ambient particulates with median aerodynamic diameters of <10 μm or <2.5 μm from the Sydney metropolitan region (Sydney PM10 or PM2.5), to traffic-derived particulates from the exhaust stack of a motorway tunnel or to inert carbon black as a control. Sydney PM10 strongly stimulated messenger RNA expression and secretion of the pro-inflammatory cytokines interleukin 6 (IL-6) and chemokine (C-X-C motif) ligand 1 (CXCL1) by mouse tracheal AEC. In contrast, traffic-derived particulates did not. Similarly, PM10 stimulated expression of IL6, IL8 and IL1B by human AEC. Mass spectrometric analysis showed that PM10 contained much higher levels of elements associated with dusts of geological origin. In contrast, tunnel soot contained much higher levels of various organic compounds, notably including long straight-chain alkanes and diesel-derived polycyclic aromatic hydrocarbons. Sydney PM2.5, as well as PM10 collected during a period including a major dust storm, both of which contained relatively lower levels of iron but similar levels of other crustal elements, did not stimulate expression or secretion of CXCL1 by mouse AEC. Ambient PM10 is likely to be more important than traffic-derived PM in causing injury to AEC leading to production of pro-inflammatory cytokines. The injurious effects may be related to the presence of iron in the coarse fraction of airborne PM. These findings are likely to be relevant to the pathogenesis of asthma.
Publisher: American Physiological Society
Date: 10-2022
DOI: 10.1152/AJPLUNG.00230.2022
Abstract: Primary bronchial epithelial cells (pBECs) obtained from donors have limited proliferation capacity. Recently, conditional reprogramming (CR) technique has overcome this and has provided the potential for extended passaging and subsequent differentiation of cells at air-liquid interface (ALI). However, there has been no donor-specific comparison of cell morphology, baseline gene expression, barrier function, and antiviral responses compared with their “parent” pBECs, especially cells obtained from donors with asthma. We, therefore, collected and differentiated pBECs at ALI from mild donors with asthma ( n = 6) for the parent group. The same cells were conditionally reprogrammed and later differentiated at ALI. Barrier function was measured during the differentiation phase. Morphology and baseline gene expression were compared at terminal differentiation. Viral replication kinetics and antiviral responses were assessed following rhinovirus (RV) infection over 96 h. Barrier function during the differentiation phase and cell structural morphology at terminal differentiation appear similar in both parent and CR groups, however, there were elongated cell structures superficial to basal cells and significantly lower FOXJ1 expression in CR group. IFN gene expression was also significantly lower in CR group compared with parent asthma group following RV infection. The CR technique is a beneficial tool to proliferate pBECs over extended passages. Considering lower FOXJ1 expression, viral replication kinetics and antiviral responses, a cautious approach should be taken while choosing CR cells for experiments. In addition, as lab-to-lab cell culture techniques vary, the most appropriate technique must be utilized to best match in idual cell functions and morphologies to address specific research questions and experimental reproducibility across the labs.
Publisher: Wiley
Date: 12-2002
DOI: 10.1046/J.1365-2222.2002.01556.X
Abstract: Epidemics of acute asthma associated with thunderstorms occur intermittently worldwide, though airway inflammation during these acute episodes has not been characterized. The aim of this study was to characterize airway inflammation in thunderstorm asthma. Cases were recruited after presentation to the emergency room with acute asthma immediately following a thunderstorm (n = 6). They were compared to two control groups: a group of atopic asthmatics that had presented with acute asthma to the emergency room prior to the thunderstorm (n = 12), and a second group of corticosteroid naive asthmatics who presented to the emergency room in the prior 12 months (n = 6). Subjects had spirometry, sputum induction and allergy skin tests acutely and at review 4 weeks later. Thunderstorm (TS) cases were more likely to have a history of hay fever and grass pollen allergy, and less likely to be on inhaled corticosteroids (ICS) prior to presentation. Cases and control groups had a similar degree of moderate to severe acute airway obstruction (P = 1.0). TS cases had elevated sputum eosinophils (14.8% of total cell count) compared to controls (1%, 2.6%, P < 0.01). TS cases had higher sputum eosinophil cationic protein (ECP 11,686 ng/mL) compared to controls (1,883, 3,300, P = 0.02) acutely. TS cases had more cells positive for IL-5 (30%) compared to controls (1, 1.5%, P = 0.02). When adjusted for ICS use, TS cases had a risk ratio for elevated sputum eosinophils of 2.4 (1.23-4.69). Thunderstorm asthma is characterized by airway inflammation with IL-5-mediated sputum eosinophilia and eosinophil degranulation. These results are consistent with allergen exposure as the cause of the exacerbation, and are consistent with the thunderstorm-induced grass pollen deluge as the cause of epidemic asthma after thunderstorms.
Publisher: Elsevier BV
Date: 10-2004
DOI: 10.1016/J.RMED.2004.07.002
Abstract: Allergic bronchopulmonary aspergillosis (ABPA) is a complex condition that affects people with asthma and cystic fibrosis (CF). It results from exposure to the fungus Aspergillus fumigatus, which leads to worsening airway inflammation and progressive damage to the lungs. The aim of this review is to outline the pathogenesis of the disorder, diagnostic criteria and to discuss the use of anti-fungal agents in its treatment. The Cochrane library of systematic reviews and the Cochrane database of controlled trials were searched for controlled trials on ABPA and its treatment in both asthma and CF. In addition, articles included within the reviews were examined separately, and a separate search carried out using Medline. A systematic review for the use of azole anti-fungal agents in ABPA was identified for their use in both CF and non-CF-related disease. The review of ABPA alone identified two randomized-controlled trials of itraconazole in chronic disease. These trials demonstrated improvements in symptoms and immune activation, but were short-term trials and failed to show a significant change in lung function. No trials were identified in CF. The use of anti-fungal agents in ABPA seems to be a rational one, with short-term efficacy demonstrated for the use of itraconazole. Further investigations are required to identify in iduals who will benefit most from treatment and to establish the correct dose and means of delivering treatment in ABPA. Longer-term studies are required to demonstrate that treatment modifies the progressive decline in lung function seen with the disease.
Publisher: CRC Press
Date: 23-06-2014
DOI: 10.1201/B16778-5
Publisher: Hindawi Limited
Date: 08-01-2022
DOI: 10.1111/HSC.13714
Abstract: Cystic fibrosis (CF) is Australia's most common life limiting genetic condition, characterised by declining health and quality of life (QoL) over time. Despite improvements in treatment, there remains no cure. Adolescents and young adults (AYAs) with CF experience broad impacts to psychosocial functioning and QoL, as well as major transitions in care, all at a time of significant developmental change. The importance of developmentally tailored approaches to youth health care and self-management for young people with CF are well understood. However, to date, models of youth specific self-management have been lacking and motivation for young people with CF has not been well explored. This qualitative study, based on a social constructionist epistemological framework, addresses this gap. A total of 21 AYAs aged 15-30 years were recruited through one paediatric and one adult Australian CF centre. Demographic, clinical and distress data were captured to describe health complexity. Semi-structured interviews were audio-recorded, transcribed and analysed using thematic analysis. Participants were representative of Australian AYAs with CF by demography and clinical status. Alarmingly, over a third reported clinically significant distress. Two themes emerged. The first Identified impacts to motivation and self-management resulting from the challenges of managing CF, life and care. These included time and competing priorities, changing health statis, mental health, social factors, unmet needs and health system complexity. The second identified factors that support motivation including: achievement, meaning and purpose consequence avoidance and accountability. These results illustrate the importance of AYA specific, theoretically founded, holistic self-management models which extend beyond current theoretical approaches that aim to understand behaviour change or address barriers, in isolation from motivation. Improved approaches to care based on these findings are essential to foster positive behavioural change, support self-management and foster the best health outcomes for young people living with CF.
Publisher: Wiley
Date: 11-2017
DOI: 10.1111/RESP.13206_7
Publisher: Wiley
Date: 23-03-2012
Publisher: Elsevier
Date: 2019
Publisher: Informa UK Limited
Date: 14-04-2016
DOI: 10.1586/17512433.2016.1172208
Abstract: Severe asthma is a complex multifactorial disease that requires specialist multidisciplinary input for optimal clinical outcomes. Following multidimensional assessment for optimisation of current therapy, self-management skills and comorbidities, all patients should be accurately phenotyped. Only after this assessment has been completed should new monoclonal antibody therapies be considered. In this review, we summarise the new antibody approaches targeting identified pathological pathways in severe refractory asthma.
Publisher: Wiley
Date: 03-12-2011
DOI: 10.1111/J.1365-2222.2010.03669.X
Abstract: The role of toll-like receptors (TLRs) and innate immune activation in clinical asthma exacerbations and their relationship to virus infection are unclear. This study aimed to characterize TLR expression and innate immune activity during virus infection in acute asthma. Subjects with acute asthma, stable asthma and healthy controls were recruited and underwent spirometry and sputum induction with isotonic saline. Selected sputum was dispersed with dithiothreitol and total and differential leucocyte counts were performed. Selected sputum was also used for quantitative real-time PCR for TLR2, TLR3, TLR4, IL-10 and IP-10mRNA expression. Sputum supernatant was used for the measurement of innate immune markers, including IL-8, matrix metalloproteinase-9 and neutrophil elastase activity. Viruses were detected using real-time and gel-based PCR. Sputum TLR2 mRNA expression was up-regulated in both acute and stable asthma compared with healthy controls and decreased 4-6 weeks after acute exacerbation. Sputum TLR2 mRNA expression was elevated in viral, compared with non-viral, acute asthma. Sputum TLR3 mRNA expression was similar in controls, stable and acute asthma. However, in acute asthma, subjects with virus-induced acute asthma had significantly higher sputum TLR3 mRNA expression. Induced sputum gene expression for IP-10 and IL-10 were increased in viral, compared with non-viral, acute asthma. In virus-induced acute asthma, levels of IP-10 and IL-10 mRNA expression were correlated with the mRNA expression of TLR2 and TLR3. Virus-induced acute asthma leads to specific induction of TLR2, TLR3, IP-10 and IL-10, suggesting that signalling via TLRs may play an important role in mediating airway inflammation, via both innate and adaptive pathways, in virus-induced exacerbations. These mediators may provide potential treatment targets for virus-induced asthma. They may also be useful in diagnosing the nature of acute asthma exacerbations and monitoring treatment responses, which would be useful in the clinical management of asthma exacerbations.
Publisher: Wiley
Date: 06-2002
DOI: 10.1046/J.1440-1843.2002.00380.X
Abstract: Interleukin (IL)-5 measurement in sputum s les has produced variable results that appear to be due to methodological problems. The aim of the present study was to investigate the effects of dithiothreitol (DTT), sputum protease inhibition and s le storage on IL-5 recovery in order to develop a method to accurately measure IL-5 in dispersed sputum supernatant. Measurement of IL-5 in sputum was performed in 22 subjects with airway disease. Interleukin-5 recovery was measured in s les spiked with recombinant human IL-5 using a commercial ELISA. A mix of four protease inhibitors (PI) was added to sputum processed using the selection method with dispersion using DTT and stored with and without inhibitors. The addition of PI to sputum resulted in a 24% increase in IL-5 recovery. Recovery was not further increased with the addition of a blocking protein. Storage of IL-5-spiked sputum gave significantly less recovery. The addition of PI to sputum processed with DTT had no effect on total cell count, viability or cell differential. Interleukin-5 recovery is increased by the addition of PI to s les processed using the selected portion method with DTT dispersion. A protease inhibitor cocktail should be added to sputum for IL-5 assay.
Publisher: MDPI AG
Date: 14-12-2015
DOI: 10.3390/V7122961
Publisher: BMJ
Date: 24-06-2015
Publisher: American Thoracic Society
Date: 03-2021
Publisher: Informa UK Limited
Date: 31-05-2020
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: European Respiratory Society
Date: 28-09-2019
Publisher: Cambridge University Press (CUP)
Date: 2018
No related grants have been discovered for Peter Wark.