67 results found
Allden SJ, Ogger PP, Ghai P, et al., 2019, The Transferrin Receptor CD71 Delineates Functionally Distinct Airway Macrophage Subsets during Idiopathic Pulmonary Fibrosis., Am J Respir Crit Care Med
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defence of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor-1 (CD71)-expressing AMs in IPF is not known. OBJECTIVES: To assess the role of CD71 expressing AMs in the IPF-lung. METHODS: We utilized multi-parameter flow cytometry, gene expression analysis and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing, or lacking, CD71 in the BAL of patients with IPF or healthy controls. MEASUREMENTS AND MAIN RESULTS: There was a distinct increase in proportions of AMs lacking CD71 in IPF patients in comparison to healthy controls. Levels of BAL transferrin were enhanced in IPF-BAL and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally and transcriptionally distinct, with CD71- AMs characterised by reduced expression of markers of macrophage maturity, impaired phagocytosis and enhanced expression of pro-fibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. CONCLUSIONS: Taken together these data highlight how CD71 delineates AM subsets which play distinct roles in IPF and furthermore, CD71- AMs may be an important pathogenic component of fibrotic lung disease.
Segal LN, Molyneaux PL, 2019, The Challenging Road of Moving from Association to Causation for Microbiome Research in Idiopathic Pulmonary Fibrosis., Am J Respir Crit Care Med, Vol: 199, Pages: 1054-1056
Moore C, Blumhagen RZ, Yang IV, et al., 2019, Resequencing study confirms host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
RATIONALE: Several common and rare genetic variants have been associated with Idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. OBJECTIVE: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. METHODS: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (N=3,624) and controls (N=4,442) across genes and regions previously associated with disease. We tested for association between disease and a) individual common variants via logistic regression and b) groups of rare variants via a sequence kernel association test. MEASUREMENTS AND MAIN RESULTS: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant, rs35705950, with an OR of 5.45 (95% CI: 4.91-6.06) for one copy of the risk allele and 18.68 (95% CI: 13.34-26.17) for two copies of the risk allele (p=9.60 x 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in risk of IPF in the TERT and RTEL1 gene regions, and found that the FAM13A and TERT regions have independent common and rare variant signals. CONCLUSIONS: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions; these genetic variants focus on biological mechanisms of host defense and cell senescence.
Garner JL, Garner SD, Hardie RJ, et al., 2019, Evaluation of a re-useable bronchoscopy biosimulator with ventilated lungs, ERJ Open Research, Vol: 5, ISSN: 2312-0541
Background: Restrictions on respiratory trainee time and access to procedures reduce the opportunities toacquire necessary skills in bronchoscopy. Simulation, not subject to such impediments, is a usefulsupplementary aid to teaching bronchoscopic techniques in a safe environment but there is a limitedchoice of simulators that are sufficiently realistic and not prohibitively expensive. This study evaluated alow-cost device that simulates an intubated and ventilated patient, employing re-useable, inflatable,BioFlex-preserved, porcine lungs.Methods: 26 bronchoscopists, trainee and experienced, after using the bronchoscopy biosimulator,completed a questionnaire using a five-point Likert scale comparing its performance with that of thecomputerised CAE AccuTouch.Results: Participants were largely positive about their experience (mean score of 4.76). The bronchoscopybiosimulator was found to be realistic (mean score 4.64), easy to use (mean score 4.88), and helpful inlearning to perform a variety of diagnostic and therapeutic procedures (mean score 4.85). Importantly, thebronchoscopy biosimulator compared favourably to the computer simulator (mean score 4.84).Conclusions: These data support the concept of the bronchoscopy biosimulator as an acceptable modelwith which to supplement the experience of bronchoscopic procedures.
Mackintosh JA, Desai SR, Adamali H, et al., 2019, In Patients with Idiopathic Pulmonary Fibrosis the Presence of Hiatus Hernia is Associated with Disease Progression and Mortality., Eur Respir J
Lukey PT, Harrison SA, Yang S, et al., 2019, A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis., Eur Respir J, Vol: 53
Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.
Macaluso C, Furcada JM, Alzaher O, et al., 2019, The potential impact of azithromycin in idiopathic pulmonary fibrosis, EUROPEAN RESPIRATORY JOURNAL, Vol: 53, ISSN: 0903-1936
Visca D, Mori L, Tsipouri V, et al., 2018, Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label mixed-method, crossover randomised controlled trial, LANCET RESPIRATORY MEDICINE, Vol: 6, Pages: 759-770, ISSN: 2213-2600
Celada LJ, Kropski JA, Herazo-Maya JD, et al., 2018, PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production., Sci Transl Med, Vol: 10
Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1+CD4+ T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4+ T cells. PD-1+ T helper 17 cells are the predominant CD4+ T cell subset expressing TGF-β. Coculture of PD-1+CD4+ T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4+ T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1+CD4+ T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
Sun J, Herazo-Maya JD, Molyneaux PL, et al., 2018, Regularized Latent Class Model for Joint Analysis of High-Dimensional Longitudinal Biomarkers and a Time-to-Event Outcome., Biometrics
Although many modeling approaches have been developed to jointly analyze longitudinal biomarkers and a time-to-event outcome, most of these methods can only handle one or a few biomarkers. In this article, we propose a novel joint latent class model to deal with high dimensional longitudinal biomarkers. Our model has three components: a class membership model, a survival submodel, and a longitudinal submodel. In our model, we assume that covariates can potentially affect biomarkers and class membership. We adopt a penalized likelihood approach to infer which covariates have random effects and/or fixed effects on biomarkers, and which covariates are informative for the latent classes. Through extensive simulation studies, we show that our proposed method has improved performance in prediction and assigning subjects to the correct classes over other joint modeling methods and that bootstrap can be used to do inference for our model. We then apply our method to a dataset of patients with idiopathic pulmonary fibrosis, for whom gene expression profiles were measured longitudinally. We are able to identify four interesting latent classes with one class being at much higher risk of death compared to the other classes. We also find that each of the latent classes has unique trajectories in some genes, yielding novel biological insights.
Molyneaux PL, Maher TM, 2018, Could quality be the key in connective tissue disease-associated interstitial lung disease?, RESPIROLOGY, Vol: 23, Pages: 801-802, ISSN: 1323-7799
Mallia P, Webber J, Gill SK, et al., 2018, Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 142, Pages: 815-+, ISSN: 0091-6749
Singanayagam A, Woodcock HV, Molyneaux PL, et al., 2018, Review of the British Thoracic Society Winter Meeting 2017, 6-8 December 2017, London, UK., Thorax, Vol: 73, Pages: 872-876
This article reviews the British Thoracic Society Winter Meeting 2017 and summarises the new developments in scientific and clinical research across the breadth of respiratory medicine. The article discusses a number of symposia and selected abstract presentations from the meeting.
Newton CA, Molyneaux PL, Oldham JM, 2018, Clinical Genetics in Interstitial Lung Disease., Front Med (Lausanne), Vol: 5, ISSN: 2296-858X
Interstitial lung disease (ILD) comprises a heterogeneous group of diffuse parenchymal lung processes with overlapping clinical, radiographic, and histopathologic features. Among the most common and deadly ILDs are idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (CHP). As the name implies, the cause of IPF remains elusive, but a variety of genetic and infectious risk factors have been identified. CHP results from chronic inhalation of an organic antigen, usually of avian or mold origin, and may occur in patients with a genetic predisposition. While IPF is treated with anti-fibrotic compounds, CHP is generally treated by suppression of the immune system and elimination of the causative antigen. Despite advances in our understanding of IPF and CHP, there exists substantial variability in the diagnosis and treatment of these disease processes. Furthermore, IPF and CHP natural history and treatment response remain far from uniform, leaving it unclear which patients derive the most benefit from disease-specific therapy. While clinical prediction models have improved our understanding of outcome risk in patients with various forms of ILD, recent advances in genomic technology provides a valuable opportunity to begin understanding the basis for outcome variability. Such advances will ultimately allow for the incorporation of genomic markers into risk stratification and clinical decision-making. In this piece, we highlight recent advances in our understanding of the genomic factors that influence susceptibility and outcome risk among patients with IPF and CHP. Genomic modalities used to identify these genomic markers include genome-wide association studies, analyses of gene expression, drug-gene interaction testing, telomere length determination, telomerase mutation analysis, and studies of the lung microbiome. We then identify gaps in knowledge that should be addressed to help facilitate the incorporation of these genomic technologies into ILD
Maher TM, Oballa E, Simpson JK, et al., 2017, An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study, LANCET RESPIRATORY MEDICINE, Vol: 5, Pages: 946-955, ISSN: 2213-2600
Herazo-Maya JD, Sun J, Molyneaux PL, et al., 2017, Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study, LANCET RESPIRATORY MEDICINE, Vol: 5, Pages: 857-868, ISSN: 2213-2600
Allen RJ, Porte J, Braybrooke R, et al., 2017, Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study, LANCET RESPIRATORY MEDICINE, Vol: 5, Pages: 869-880, ISSN: 2213-2600
Molyneaux PL, Maher TM, 2017, Time for an International Consensus on Hypersensitivity Pneumonitis. A Call to Arms., American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 665-666, ISSN: 1073-449X
Salisbury ML, Han MK, Dickson RP, et al., 2017, Microbiome in interstitial lung disease: from pathogenesis to treatment target., Curr Opin Pulm Med, Vol: 23, Pages: 404-410
PURPOSE OF REVIEW: This review summarizes current knowledge of the role of the lung microbiome in interstitial lung disease and poses considerations of the microbiome as a therapeutic target. RECENT FINDINGS: Although historically considered sterile, bacterial communities have now been well documented in lungs in health and disease. Studies in idiopathic pulmonary fibrosis (IPF) suggest that increased bacterial burden and/or abundance of potentially pathogenic bacteria may drive disease progression, acute exacerbations, and mortality. More recent work has highlighted the interaction between the lung microbiome and the innate immune system in IPF, strengthening the argument for the role of both host and environment interaction in disease pathogenesis. In support of this, studies of interstitial lung diseases other than IPF suggest that it may be the host immune response, which shapes the microbiome in these diseases. Some clinical and mouse model data also suggest that the lung microbiome may represent a therapeutic target, via antibiotic administration, immunization against pathogenic organisms, or treatment directed at gastroesophageal reflux. SUMMARY: Evidence suggests that the lung microbiome may serve as a prognostic biomarker, a therapeutic target, or provide an explanation for disease pathogenesis in IPF.
Conforti F, Davies ER, Calderwood CJ, et al., 2017, The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis, ONCOTARGET, Vol: 8, Pages: 48737-48754, ISSN: 1949-2553
Molyneaux PL, Willis-Owen SAG, Cox MJ, et al., 2017, Host-Microbial Interactions in Idiopathic Pulmonary Fibrosis, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 195, Pages: 1640-1650, ISSN: 1073-449X
Hewitt RJ, Molyneaux PL, 2017, The respiratory microbiome in idiopathic pulmonary fibrosis, ANNALS OF TRANSLATIONAL MEDICINE, Vol: 5, ISSN: 2305-5839
Faner R, Sibila O, Agustí A, et al., 2017, The microbiome in respiratory medicine: current challenges and future perspectives., Eur Respir J, Vol: 49
The healthy lung has previously been considered to be a sterile organ because standard microbiological culture techniques consistently yield negative results. However, culture-independent techniques report that large numbers of microorganisms coexist in the lung. There are many unknown aspects in the field, but available reports show that the lower respiratory tract microbiota: 1) is similar in healthy subjects to the oropharyngeal microbiota and dominated by members of the Firmicutes, Bacteroidetes and Proteobacteria phyla; 2) shows changes in smokers and well-defined differences in chronic respiratory diseases, although the temporal and spatial kinetics of these changes are only partially known; and 3) shows relatively abundant non-cultivable bacteria in chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis and bronchiectasis, with specific patterns for each disease. In all of these diseases, a loss of diversity, paralleled by an over-representation of Proteobacteria (dysbiosis), has been related to disease severity and exacerbations. However, it is unknown whether dysbiosis is a cause or a consequence of the damage to bronchoalveolar surfaces.Finally, little is known about bacterial functionality and the interactions between viruses, fungi and bacteria. It is expected that future research in bacterial gene expressions, metagenomics longitudinal analysis and host-microbiome animal models will help to move towards targeted microbiome interventions in respiratory diseases.
Molyneaux PL, Cox MJ, Wells AU, et al., 2017, Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis, RESPIRATORY RESEARCH, Vol: 18, ISSN: 1465-993X
Russell A-M, Adamali H, Molyneaux PL, et al., 2016, Daily Home Spirometry: An Effective Tool for Detecting Progression in Idiopathic Pulmonary Fibrosis, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 194, Pages: 989-997, ISSN: 1073-449X
Fingerlin TE, Zhang W, Yang IV, et al., 2016, Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia, BMC GENETICS, Vol: 17, ISSN: 1471-2156
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Chronic or heavy smoking can lead to different forms of pathologic remodeling in the airways and distal lung. There is an 8% to 19% prevalence of interstitial lung disease (ILD) in chronic smokers who were unaware that they had a lung disorder. Descriptive pathologic and radiologic analyses have enabled a number of clinical diseases to be identified and grouped within a range of smoking-related ILDs. We review the radiology, pathology, and clinical management of pulmonary Langerhans cell histiocytosis, respiratory bronchiolitis-associated ILD, and desquamative interstitial pneumonia. We discuss the difficulties of classification and also where the new entity of airspace enlargement with fibrosis fits into the current grouping. The prognosis for these conditions is variable depending on the intrinsic behavior of each condition. Smoking cessation is the first-line therapy of choice for any smoking-related ILD, whereas treatment with corticosteroids and other agents forms an important, but occasionally futile, intervention.
© 2016 Wolters Kluwer Health, Inc. Hypersensitivity pneumonitis (HP) is a syndrome caused by an exaggerated immune response to the inhalation and subsequent sensitization to a variety of environmental antigenic particles. The pathogenesis remains unclear; however, a "two-hit hypothesis" implicating a pathologic interaction between an environmental antigen and the immune system of a susceptible host seems likely as only a minority of the exposed individuals develop HP. The presentation may be acute, as in bird fancier's lung, the classical form of HP, or more insidiously as the subacute form of chronic HP caused by repeated lowlevel antigenic exposure. Despite these categorizations, there is frequently an overlap between the clinical entities and no guaranteed linear progression through the different pathologic stages. Prompt diagnosis is crucial, and is based on an exposure history, precipitating antibodies to the offending antigen, and a combination of clinical, radiologic, and physiological findings. The mainstay of treatment is allergen avoidance, but systemic steroids are of value for both the subacute and the chronic forms, although they do not alter the longterm outcome. This review summarizes the current knowledge of the pathophysiology of HP and the main entities in the differential diagnosis.
Hashim HH, Molyneaux PL, Regan S, et al., 2015, BONE PROTECTION IN ORAL CORTICOSTEROID DEPENDANT ASTHMATICS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A157-A158, ISSN: 0040-6376
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