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Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.

Rationale: Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with COVID-19. We hypothesised that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with anti-inflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalised with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomised controlled platform trial in hospitalised patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139+SoC vs 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure, and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc ANCOVA over days 2–7: p=0.0099 vs SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy and major organ function were evaluated. Conclusions: In COVID pneumonitis, inhaled GB013 was well-tolerated, achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT04473053. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).Keywords: Covid-19; Galectin-3; GB0139

Janus kinase inhibitors (JAKi) are an exciting option for the treatment of rheumatoid arthritis (RA) but little is known about their safety and tolerability in patients with existing respiratory disorders. The objective was to compare pulmonary safety of JAKi versus rituximab in patients with concurrent interstitial lung disease (ILD) or bronchiectasis. We performed a retrospective electronic patient record review of patients with known ILD or bronchiectasis commencing JAKi or rituximab for the treatment of RA. Patients initiating treatment from January 2016 to February 2020 were included. Respiratory events (hospitalization or death from a respiratory cause) were compared using Kaplan–Meier survival analysis. We analysed patients who received JAKi (n = 28) and rituximab (n = 19) for a mean (SD) of 1.1 (0.62) and 2.14 (1) years respectively. Patients were predominantly female (68%), anti-CCP antibody positive (94%) and non-smoking (89%) with a median (IQR) percentage predicted FVC at baseline of 100% (82–115%) and percentage predicted TLCO of 62% (54.5–68%). Respiratory events occurred in five patients treated with JAKi (18%; 5 hospitalizations, 2 deaths) and in four patients treated with rituximab (21%; 3 hospitalizations, 1 death). Respiratory event rates did not differ between groups (Cox-regression proportional hazard ratio = 1.38, 95% CI 0.36–5.28; p = 0.64). In this retrospective study, JAKi for the treatment of RA with existing ILD or bronchiectasis did not increase the rate of hospitalization or death due to respiratory causes compared to those treated with rituximab. JAK inhibition may provide a relatively safe option for RA in such patients.

Acute Respiratory Distress Syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, has no cure. Hypoxemia is a defining feature, yet its impact on inflammation is often neglected. Patients with ARDS are monocytopenic early in the onset of the disease. Endotoxin or Streptococcus pneumoniae acute lung injury (ALI) in the context of hypoxia replicates this finding, through hypoxia-driven suppression of type I interferon signalling. This results in failed lung monocyte-derived interstitial macrophages (IM) niche expansion and unchecked neutrophilic inflammation. Administration of colony stimulating factor 1 (CSF1) rescues the monocytopenia, alters the circulating classical monocyte phenotype in hypoxic endotoxin-driven ALI and enables lung IM population expansion, thus limiting lung injury in endotoxin- and virally-induced hypoxic ALI. Hypoxia directly alters immune dynamics to the detriment of the host and manipulation of this aberrant response offers new therapeutic strategies for ARDS.

RationaleHigh galectin-3 levels predict poor outcomes in patients with COVID-19. Galectin-3 activates monocytes and macrophages which are directly implicated in COVID-19 immunopathology and the cytokine storm. GB0139 is a potent thiodigalactoside galectin-3 inhibitor and may reduce the severe effects of the disease. We report safety and pharmacokinetics and pharmacodynamics of the inhaled galectin-3 inhibitor, GB0139, and assess clinical outcomes and key systemic inflammatory biomarkers in hospitalised patients with COVID-19 (ClinicalTrials.gov/EudraCT identifier: NCT04473053/2020-002230-32).MethodsAdults with COVID-19 requiring oxygen, and with pneumonitis on x-ray, were randomised to receive standard of care (SOC; including dexamethasone; n=21) or SOC plus 10 mg GB0139 twice daily for 48 hours, then once daily for ≤14 days (n=20).ResultsPatients aged 27–87 years were enrolled from July 2020; the final patient completed the 90-day follow-up in April 2021. GB0139+SOC was well tolerated with no treatment-related serious adverse events reported. Incidences of adverse events were similar between treatment arms (40 with GB0139+SOC vs 35 with SOC). Plasma GB0139 was measurable in all patients after inhaled exposure, with moderate interpatient variability, and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc over days 2–7: p=0·0099 vs SOC). Rate of decline in fraction of inspired oxygen (%) requirement was significantly greater in the GB0139+SOC arm with a posterior mean difference of -1·51 (95% highest posterior density: -2·90, -0·189) versus SOC. Plasma levels of biomarkers associated with inflammation, coagulopathy, major organ function and fibrosis showed a downward trend versus SOC.ConclusionsGB0139+SOC was well tolerated and achieved clinically relevant plasma concentrations and target engagement. This, and the reduction in markers associated with inflammatory, coagulation, fibrosis, and reduction in inspired oxygen (%) over SOC alone, indicates the therapeutic potential for inhaled GB0139 in hospitalised patients with COVID-19.

BackgroundChronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) are chronic, progressive lung ailments which are characterized by distinct pathologies. Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking. Exosomes are small extracellular vesicles attributed to carry proteins, mRNA, miRNA and sncRNA to facilitate cell-to-cell communication under normal and diseased conditions. Exosomal miRNAs have been studied in relation to many diseases. However, there is little to no knowledge regarding the miRNA population of BALF or the lung tissue derived exosomes in COPD and IPF. Here, we determined and compared the miRNA profiles of BALF and lung tissue-derived exosomes from healthy non-smokers, healthy smokers, and patients with COPD and IPF in independent cohorts.ResultsExosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were approximately 89.85 nm in size and ∼2.95 × 1010 particles/mL. Lung-derived exosomes were ∼146.04 nm in size and ∼2.38 × 1011 particles/mL. NGS results identified three differentially expressed miRNAs in the BALF, while one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers. Of these, three- and five-fold downregulation of miR-122-5p amongst the lung tissue-derived exosomes from COPD patients as compared to healthy non-smokers and smokers, respectively. Interestingly, there were key 55 differentially expressed miRNAs in the lung tissue-derived exosomes of IPF patients compared to non-smoking controls.ConclusionsOverall, we identified specific miRNAs to develop as biomarkers or targets for pathogenesis of these chronic lung diseases.

IntroductionCOVID-19 (Coronavirus Disease 2019) is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS CoV2 (Severe Acute Respiratory Syndrome Coronavirus 2). At present there are few proven effective treatments. This early phase experimental medicine protocol describes an overarching and adaptive trial designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy, which may support further development and deployment of candidate therapies in larger scale trials of COVID-19 positive patients.Methods and analysisDEFINE is an ongoing exploratory multicentre platform, open label, randomised study. COVID-19 positive patients will be recruited from the following cohorts; a) community cases b) hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT) scan or requiring supplemental oxygen and c) hospitalised patients requiring assisted ventilation. Participants may be recruited from all three of these cohorts, depending on the experimental therapy, its route of administration and mechanism of action.The primary statistical analyses are concerned with the safety of candidate agents as add-on therapy to standard of care in patients with COVID-19.Safety will be assessed usingHaematological and biochemical safety laboratory investigations.Physical examinationVital signs (blood pressure/heart rate/temperature and respiratory rate)Daily electrocardiogram (ECG) readingsAdverse eventsThe analysis population will consist of (i) all patients randomised to a treatment arm who receive any dose of the study drug and (ii) all patients randomised to the control arm who would also have been eligible to receive a study drug.Secondary analysis will assess the following variables during treatment period 1) the response of key exploratory biomarkers 2) change in WHO ordinal scale and NEWS2 score 3) oxygen requirements 4) viral load 5) duration of hospital stay 6) PK/PD and 7) changes in key coagulation pathways.Ethics and disseminationThe DEFINE trial platform and its initial two treatment and standard of care arms have received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian and NHS Greater Glasgow and Clyde.The results of each study arm will be published as soon as the treatment arm has finished recruitment, data input is complete and any outstanding patient safety follow-ups have been completed. Depending on the results of these or future arms, data will be shared with larger clinical trial networks, including RECOVERY, and to other partners for rapid roll out in larger patient cohorts.Registration detailsThe DEFINE protocol has been registered on ISRCTN (https://www.isrctn.com/) and Clinicaltrials.gov(https://www.clinicaltrials.gov/).ClinicalTrials.gov Identifier: NCT04473053ISRCTN Identifier: ISRCTN14212905Strengths and limitations of this studyThe trial is as flexible as possible to ensure a broad range of patients can be recruited and candidate therapies can be added or removed as evidence emerges.The team are collecting real world data of medications at an early stage of their use in COVID-19 across the full spectrum of disease; allowing the administration of different treatment formulations (inhaled vs oral vs intravenous).The simultaneous collection of clinical outcomes as well as exploratory endpoints including clinical biomarkers, flow cytometry, PK/PD and thromboelastography allows further characterisation and elucidation of the temporal immuno-inflammatory cascade in COVID-19 to inform on future therapy selection.This is a Phase 1b/IIa platform study and thus the primary end point is clinical safety therefore our anticipated numbers will be too small to allow for definitive data on efficacy.DEFINE is an experimental medicine platform, currently restricted to three clinical sites and so the generation of data will be slower than that of larger platforms with access to a greater number of patients.

Galectin (Gal)-3 is a profibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small-molecule inhibitor of Gal-3.A randomised, double-blind, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15–50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once-daily doses of TD139 (0.3–10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration (Cmax) values ranging from 0.6 to 3 h and a plasma half-life (T1/2) of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 and 10 mg dose groups compared with placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (platelet-derived growth factor-BB, plasminogen activator inhibitor-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic, progressive lung ailments that are characterized by distinct pathologies. Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking. Extracellular vesicles (EVs), including exosomes, are small, lipid-bound vesicles attributed to carry proteins, lipids, and RNA molecules to facilitate cell-to-cell communication under normal and diseased conditions. Exosomal miRNAs have been studied in relation to many diseases. However, there is little to no knowledge regarding the miRNA population of bronchoalveolar lavage fluid (BALF) or the lung-tissue-derived exosomes in COPD and IPF. Here, we determined and compared the miRNA profiles of BALF- and lung-tissue-derived exosomes of healthy non-smokers, smokers, and patients with COPD or IPF in independent cohorts. Results: Exosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were ~89.85 nm in size with a yield of ~2.95 × 1010 particles/mL in concentration. Lung-derived exosomes were larger in size (~146.04 nm) with a higher yield of ~2.38 × 1011 particles/mL. NGS results identified three differentially expressed miRNAs in the BALF, while there was one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers. Of these, miR-122-5p was three- or five-fold downregulated among the lung-tissue-derived exosomes of COPD patients as compared to healthy non-smokers and smokers, respectively. Interestingly, there were a large number (55) of differentially expressed miRNAs in the lung-tissue-derived exosomes of IPF patients compared to non-smoking controls. Conclusions: Overall, we identified lung-specific miRNAs associated with chronic lung diseases that can serve as potential biomarkers or therapeutic targets.

EgeUn###, Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: 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 control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. 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 odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 102295). 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 the TERT and RTEL1 gene regions in the risk of IPF, 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, and these genetic variants focus on biological mechanisms of host defense and cell senescence. Copyright © 2019 by the American Thoracic Society, Háskóli Íslands, HI University of Chicago University of Ulsan, UOU Monash University, MU University of Nottingham University of Edinburgh University of Colorado Denver Universitat de Barcelona University of Pittsburgh, Pitt Harvard School of Dental Medicine Massachusetts General Hospital, MGH University of Pennsylvania, Penn University College Cork, UCC City, University of London, City University of California, San Francisco, UCSF School of Medicine, Vanderbilt University Ege Üniversitesi University of Virginia, UV Aarhus Universitetshospital Central Manchester University Hospitals NHS Foundation Trust Columbia University Novartis Sunovion COPD Foundation Pfizer National Heart, Lung, and Blood Institute, NHLBI: R01-HL097163, UH3-HL123442, P01-HL092870 U.S. Department of Defense, DOD: W81XWH-17-1-0597, U01 HL089897, U01 HL089856 AstraZeneca Siemens Foundation North Carolina GlaxoSmithKline Foundation, 1National Jewish Health, Denver, Colorado; 2School of Public Health; 3Department of Medicine, and 54Department of Immunology, University of Colorado Denver, Denver, Colorado; 4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 5Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts; 6Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;7Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; 9Respiratory Medicine Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 10Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; 11Royal Brompton Hospital and Imperial College, London, United Kingdom; 12Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; 13Department of Medicine, University of California, San Francisco, San Francisco, California; 14Gilead Sciences, Foster City, California; 15Department of Medicine, University of Chicago, Chicago, Illinois; 16Department of Medicine, University of Virginia, Charlottesville, Virginia; 17Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; 19National Hospital Organization Tokyo National Hospital, Tokyo, Japan; 20Helmholtz Zentrum München, Neuherberg, Germany; 21University Hospital Munich, Munich, Germany; 22Department of Pulmonology, Ege University Hospital, Bornova, Izmir, Turkey; 23Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; 24Alfred Hospital and Monash University, Melbourne, Australia; 25Pulmonary Medicine, GB Morgagni Hospital, Forlì, Italy; 26Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; 27Université Paris Diderot and Hôpital Bichat, Paris, France; 28Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 29Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain; 30National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland; 31Department of Medicine, Columbia University Irving Medical Center, New York, New York; 32Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; 33Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 34Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” México City, México; 35Universidad Nacional Autónoma de México, México City, México; 36Cork University Hospital and University College Cork, Cork, Ireland; 37St. Vincent’s University Hospital, Dublin, Ireland; 38School of Medicine, University College Dublin, Dublin, Ireland; 39Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital, Prague, Czech Republic; 40University of British Columbia, Vancouver, Canada; 41Tokyo Medical and Dental University, Tokyo, Japan; 42Institute for Respiratory Health and; 43Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, Australia; 44Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 45Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia; 46Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey; 47Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 48Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany; 49Department of Medicine, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland; 50CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico; 51Department of Internal Medicine, University of Genoa, Genoa, Italy; 52Biomedical Genomics Center, University of Minnesota; Minneapolis, Minnesota; and 53Northwest Genomics Center, University of Washington, Seattle, Washington -- This research was supported by grants from the NHLBI (R01-HL097163, P01-HL092870, and UH3-HL123442) and the Department of Defense (W81XWH-17-1-0597). The COPDGene project was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. The COPDGene project was also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

The aim of this study was to compare radiology-based prediction models in rheumatoid arthritis-related interstitial lung disease (RAILD) to identify patients with a progressive fibrosis phenotype. RAILD patients had computed tomography (CT) scans scored visually and using CALIPER and forced vital capacity (FVC) measurements. Outcomes were evaluated using three techniques, as follows. 1) Scleroderma system evaluating visual interstitial lung disease extent and FVC values; 2) Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines applied to RAILD; and 3) CALIPER scores of vessel-related structures (VRS). Outcomes were compared to IPF patients. On univariable Cox analysis, all three staging systems strongly predicted outcome (scleroderma system hazard ratio (HR) 3.78, p=9×10−5; Fleischner system HR 1.98, p=2×10−3; and 4.4% VRS threshold HR 3.10, p=4×10−4). When the scleroderma and Fleischner systems were combined, termed the progressive fibrotic system (C-statistic 0.71), they identified a patient subset (n=36) with a progressive fibrotic phenotype and similar 4-year survival to IPF. On multivariable analysis, with adjustment for patient age, sex and smoking status, when analysed alongside the progressive fibrotic system, the VRS threshold of 4.4% independently predicted outcome (model C-statistic 0.77). The combination of two visual CT-based staging systems identified 23% of an RAILD cohort with an IPF-like progressive fibrotic phenotype. The addition of a computer-derived VRS threshold further improved outcome prediction and model fit, beyond that encompassed by RAILD measures of disease severity and extent., Combining the scleroderma and Fleischner staging systems in RAILD identifies patients with an IPF-like progressive fibrotic phenotype. CALIPER VRS scores further improve model fit, beyond that encompassed by RAILD measures of disease severity and extent. http://ow.ly/SUcV30mmeYI

Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs (e.g. rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally. ispartof: EUROPEAN RESPIRATORY REVIEW vol:27 issue:150 ispartof: location:England status: published

Background Silicosis is one of the oldest occupational lung diseases, but it continues to cause significant morbidity and mortality worldwide. Aims To report cases of silicosis presenting to two specialist respiratory clinics. Methods A retrospective analysis of prospectively collected data of cases of silicosis in workers referred to specialist respiratory clinics. Results Over the course of 6 years, six cases were identified. The patients were all male with an age range between 24 and 39 years. The duration of silica exposure ranged between 7 and 20 years (mean 13 years). Four cases were entirely asymptomatic at presentation, and two cases described minimal shortness of breath on exertion. Pulmonary function tests were normal in three cases, and a mild restrictive ventilatory defect was documented in the other cases. All had a low apparent predicted probability of pneumoconiosis based on health questionnaires, spirometry and duration of silica exposure. The initial chest X-ray was abnormal in all six cases with radiological evidence of silicosis (International Labour Office profusion category ≥1/1) on imaging, and all had evidence of silicosis on high-resolution computed tomography (HRCT). Three patients had already progressed to progressive massive fibrosis on HRCT scanning at the time of referral to specialist respiratory services. Conclusions The appearances of these six cases of silicosis in young, asymptomatic construction workers emphasizes the importance of enforcing effective exposure control and comprehensive surveillance programmes. Our observations highlight the importance of having a low threshold for early radiological screening to promote early and effective detection of this disease.

Background Donkey pulmonary fibrosis (DPF) is a spontaneous syndrome of aged donkeys with a high prevalence (35%). No previous detailed characterization of DPF has been performed. We sought to determine the similarities between DPF and recognized patterns of human pulmonary fibrosis. Methods Whole lungs were collected from 32 aged donkeys at routine necropsy. Gross examination revealed pulmonary fibrosis in 19 donkeys (DPF cases), whereas 13 (control cases) had grossly normal lungs. Eighteen whole inflated ex vivo lungs (11 DPF cases, seven control cases) were imaged with high-resolution CT (HRCT) scan, whereas the remainder were sectioned and photographed. Tissue samples were collected from all lungs for histopathologic evaluation using a standardized protocol. HRCT images and histology sections underwent independent blinded review. Lung tissue was analyzed for herpes virus, fungal hyphae, mycobacteria, and dust content. Results Ten of 19 DPF lungs were categorized as being consistent with pleuroparenchymal fibroelastosis (PPFE) according to previously defined histologic and imaging criteria. All 10 PPFE-like lungs had marked pleural and subpleural fibrosis, predominantly within the upper lung zone, with accompanying intraalveolar fibrosis and elastosis. Asinine herpesvirus was ubiquitously expressed within control and DPF lung tissue. No other etiologic agents were identified. Conclusions Many cases of DPF share key pathologic and imaging features with human PPFE, a rare interstitial pneumonia. Consequently, further study of DPF may help to elucidate the etiopathogenesis of human PPFE.

Very little data exists on the prevalence and impact of sleep-disordered breathing (SDB) in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to examine the impact of SDB on newly diagnosed IPF patients and explore associations with lung function parameters.From 2005 to 2009, a cohort of 27 newly diagnosed patients with IPF underwent unattended polygraphy. All patients were diagnosed according to ATS 2000 diagnostic criteria and were not on supplemental oxygen or other treatment. Standard statistical analysis was undertaken using SPSS v. 19 (IBM).Of the 27 patients, 19 were men. There was no correlation at baseline of apnoea + hypopnoea per time in bed (AH), oxygen desaturation index, or 4% desaturations with any lung function variables, age, or body mass index. Six patients had significant SDB (AH20). Two patients were started on CPAP following polygraphy. No variables from the original sleep studies at baseline predicted eventual long-term oxygen therapy (LTOT) use. At 5-year follow-up, 18 of 27 patients had died (67%). Cox regression analysis showed no association of time spent at SpO290% on baseline polygraphy with survival (p = 0.39). There was no association with survival for AH20 (p = 0.4) or LTOT use (p = 0.19).Our results do not support the contention that nocturnal upper airway obstruction in steroid-free patients with IPF is a common problem or correlated with lung function. In this cohort of patients, there was no evidence that significant SDB at baseline was a predictor of survival.

Rationale: Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury.Objectives: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation.Methods: A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [18F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours.Measurements and Main Results: As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lu...

Objective Resolution and long-term functional effects of pulmonary emboli are unpredictable. This study was carried out to assess persisting vascular bed perfusion abnormalities and resolution of arterial thrombus in patients with recent pulmonary embolism (PE). Methods and materials 26 Patients were prospectively evaluated by dynamic (4D) contrast enhanced CT perfusion dynamic pulmonary CT perfusion. Intermittent volume imaging was performed every 1.5–1.7 s during breath-hold and perfusion values were calculated by maximum-slope technique. Thrombus load (modified Miller score; MMS) and ventricular diameter were determined. Perfusion maps were visually scored and correlated with residual endoluminal filling defects. Results The mean initial thrombus load was 13.1 ± 4.6 MMS (3–16), and 1.2 ± 2.1 MMS (0–8) at follow up. From the 24 CTPs with diagnostic quality perfusion studies, normal perfusion was observed in 7 (29%), and mildly-severely abnormal in 17 (71%). In 15 patients with no residual thrombus on follow up CTPA, normal perfusion was observed in 6, and abnormal perfusion in 9. Perfusion was abnormal in all patients with residual thrombus on follow up CTPA. Pulmonary perfusion changes were classified as reduced (n = 4), delayed (systemic circulation pattern; n = 5), and absent (no-flow; n = 5). The right ventricle was dilated in 12/25 (48%) at presentation, and normal in all 26 follow up scans. Weak correlation was found between initial ventricular dilatation and perfusion abnormality at follow up (r = 0.15). Conclusions Most patients had substantial perfusion abnormality at 3–6 months post PE. Abnormal perfusion patterns were frequently observed in patients and in regions with no corresponding evidence of residual thrombus on CTPA. Some defects exhibit delayed, presumed systemic, enhancement (which we have termed ‘stunned’ lung). CT perfusion provides combined anatomical and functional information about PE resolution.

Context: The human endometrium has an exceptional capacity for repeated repair after menses, but its regulation remains undefined. Premenstrually, progesterone levels fall and prostaglandin (PG) F2α synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF2α, and hypoxia increase vascular endothelial growth factor (VEGF), an endometrial repair factor. Design and Results: Endometrial biopsies were collected (n = 47) with ethical approval and consent. VEGF mRNA, quantified by quantitative RT-PCR, was increased during menstruation (P < 0.01).VEGF protein was maximally secreted from proliferative endometrial explants. Treatment of an endometrial epithelial cell line and primary human endometrial stromal cells with 100 nm PGF2α or hypoxia (0.5% O2) resulted in significant increases in VEGF mRNA and protein. VEGF was maximal when cells were cotreated with PGF2α and hypoxia simultaneously (P < 0.05–0.001). Secretory-phase endometrial explants also showed an increase in VEGF with cotreatment (P < 0.05). However, proliferative-phase explants showed no increase in VEGF on treatment with PGF2α and/or hypoxia. Proliferative tissue was induced to increase VEGF mRNA expression when exposed to progesterone and its withdrawal in vitro but only in the presence of hypoxia and PG. Hypoxia-inducible factor-1α (HIF-1α) silencing with RNA interference suppressed hypoxia-induced VEGF expression in endometrial cells but did not alter PGF2α-induced VEGF expression. Conclusions: Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF2α, and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1α to increase VEGF, whereas PGF2α acts in a HIF-1α-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair.

After menstruation, the endometrium has a remarkable capacity for repair, but the factors involved remain undefined. We hypothesize adrenomedullin (AM) plays a role in this process. Premenstrually progesterone levels decline, stimulating prostaglandin (PG) synthesis, vasoconstriction, and hypoxia. This study aimed to determine 1) AM expression throughout the menstrual (M) cycle and 2) its regulation by PG and hypoxia. Human endometrial biopsies (n = 51) were collected with ethical approval and consent. AM mRNA expression was examined by quantitative RT-PCR and was found to be selectively elevated in endometrium from the menstrual (M) phase (P < 0.001). AM immunohistochemical staining was maximal in M and proliferative (P) endometrium. Culture of secretory, but not P, explants with 100 nm PGF2α or hypoxia (0.5% O2) increased AM mRNA (P < 0.05). P explants were induced to increase AM expression using in vitro progesterone withdrawal but required the presence of hypoxia (P < 0.05). Short hairpin sequences against hypoxia-inducible factor-1α (HIF-1α) inhibited AM hypoxic up-regulation but did not alter PGF2α-induced expression. The AM receptor was immunolocalized to endothelial cells in both lymphatic and blood vessels. Conditioned medium from PGF2α-treated cells increased endothelial cell proliferation and branching (P < 0.05). This was abolished by AM receptor antagonists. In conclusion, AM is elevated at the time of endometrial repair and induces both angiogenesis and lymphangiogenesis by stimulating endothelial cell proliferation and tube formation. In the human endometrium, AM expression is up-regulated by two mechanisms: a HIF-1α-mediated hypoxic induction and a HIF-1α-independent PGF2α pathway. These physiological mechanisms may provide novel therapeutic targets for disorders such as heavy menstrual bleeding.

An excess of neutrophils in the alveoli and lung interstitium has been described in idiopathic pulmonary fibrosis (IPF). Engagement of neutrophil Fcγ receptors with IgG complexes may contribute to the pathogenesis of IPF. The neutrophil FcγRIIIb receptor occurs in two codominantly expressed allelic variants, NA1 and NA2, which exhibit different binding affinities for IgG1 and IgG3 subclasses. The aim of this study was to investigate whether FcγRIIIb genotype is associated with IPF susceptibility or disease progression. In a case-control study we compared the distribution of FcγRIIIb NA1/2 polymorphisms in 142 patients with IPF and in 218 controls using allele-specific PCR amplification. Significant skewing in the distribution of FcγRIIIb genotypes was observed between patients with IPF and control subjects. In the IPF cohort, there was higher frequency of the NA1/NA1 genotype (0.19 vs. 0.07), and lower NA2/NA2 frequency (0.31 vs. 0.50; χ2 = 17.71, df = 2, P

AIM: To assess the feasibility of radiation dose reduction with adaptive iterative dose reduction (AIDR-6 3D) reconstruction in dynamic pulmonary CT perfusion.MATERIALS AND METHODS: CTP examinations of 10 patients acquired at 100 kVp/50 mAs were reconstructed with filtered back projection (FBP) and AIDR-3D. Artificial noise was added to raw data (pre-reconstruction projection data) to simulate lower tube current scanning. Radiodensity (in Hounsfield units), noise, and perfusion values were compared.RESULTS: There was no significant difference in noise between the full and simulated reduced tube current with AIDR-3D reconstruction (p = 1). There was significantly lower noise in lung tissue with AIDR-3D images when compared to reconstructions without AIDR-3D (p = 0.005) and no significant change in the radiodensity (p = 1; mean difference CONCLUSION: AIDR-3D produced significantly lower noise images than FBP-based algorithms and maintained consistent noise levels in lung at 12.5 mAs, indicating this algorithm is suitable for reduced dose lung perfusion imaging. Iterative reconstruction allows significant radiation dose reduction of up to fourfold in smaller patients, and up to twofold in the medium/large size patients. The increase in perfusion values at 25% simulated tube currents is attributed to attenuation bias.

Increased levels of the neutrophil chemokine interleukin (IL)-8 in the lungs of severe trauma patients can predict subsequent development of acute respiratory distress syndrome. Because the lungs of brain-dead organ donors can contain high levels of IL-8, we hypothesized that this may predispose to early graft failure in the recipient after lung transplantation. Twenty-six organ donors prospectively satisfying clinical criteria for lung donation underwent bronchoalveolar lavage and lung biopsy to determine the effect of neutrophil infiltration and IL-8 expression in the donor lung on graft function and survival in 26 respective recipients after lung transplantation. Nine recipients developed severe graft dysfunction, of whom six subsequently died (median survival: 24 d [range: 5 to 39 d]); all others survived beyond 6 mo. The IL-8 signal in the donor lung correlated with the percent neutrophils in bronchoalveolar lavage fluid (BALF) before implantation (42.4 +/- 7.24 [mean +/- SE]%, p = 0.03) and with the degree of impairment in graft oxygenation after implantation (p = 0.01). An increased level of IL-8 in the donor BALF was associated with the development of severe early graft dysfunction (p = 0.027) and with early recipient mortality (p = 0.0034). Use of donor lungs with high IL-8 levels is associated with a poor prognosis after lung transplantation. Attenuating the donor's inflammatory response before organ retrieval may improve early outcome after lung transplantation, and help maximize lung use from the existing donor pool.

Interstitial lung disease (ILD) is a common extra-articular manifestation associated with increased morbidity and mortality in patients with rheumatoid arthritis (RA). Early case reports of serious respiratory adverse events (SRAEs) following treatment with anti-TNF agents have led to concerns about biologic therapy in patients with RA-associated ILD (RA-ILD), and a tendency for biologic agents targeting factors other than TNF to be prescribed in such patients. At present, the appropriateness of such decisions is not clear. Given that the therapeutic goal for RA is remission, clinicians increasingly face the challenge of choosing the optimal biologic agent in patients with RA-ILD and uncontrolled joint disease. However, no evidence-based guidelines exist to guide physicians in deciding whether to commence biologic therapy in this setting, or in selecting which drug is most appropriate. Herein, we review the evidence for the comparative pulmonary safety of anti-TNF agents and non-TNF-targeting biologic agents in RA-ILD. In addition, we propose a framework for assessment of baseline disease severity to guide treatment decisions, and for monitoring during therapy. Because of substantial gaps in the available evidence, we also describe a research agenda aimed at obtaining data that will help inform future clinical practice.

Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell–mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.

Acute tissue injury is often considered in the context of a wound. The host response to wounding is an orchestrated series of events, the fundamentals of which are preserved across all multicellular organisms. In the human lung, there are a myriad of causes of injury, but only a limited number of consequences: complete resolution, persistent and/or overwhelming inflammation, a combination of resolution/remodelling with fibrosis or progressive fibrosis. In all cases where complete resolution does not occur, there is the potential for significant ongoing morbidity and ultimately death through respiratory failure. In this review, we consider the elements of injury, resolution and repair as they occur in the lung. We specifically focus on the role of the macrophage, long considered to have a pivotal role in regulating the host response to injury and tissue repair.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a β-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. OBJECTIVES: To examine the role of galectin-3 in pulmonary fibrosis.METHODS: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF.MEASUREMENTS AND MAIN RESULTS: Transforming growth factor (TGF)-β and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-β1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of β-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin-3, TD139, blocked TGF-β-induced β-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF.CONCLUSIONS: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF.

Exaggerated hypoxic pulmonary vasoconstriction is a key factor in the development of high altitude pulmonary edema (HAPE). Due to its effectiveness as a pulmonary vasodilator, sildenafil has been proposed as a prophylactic agent against HAPE. By conducting a parallel-group double blind, randomized, placebo-controlled trial, we investigated the effect of chronic sildenafil administration on pulmonary artery systolic pressure (PASP) and symptoms of acute mountain sickness (AMS) during acclimatization to high altitude. Sixty-two healthy lowland volunteers (36 male; median age 21 years, range 18 to 31) on the Apex 2 research expedition were flown to La Paz, Bolivia (3650 m), and after 4-5 days acclimatization ascended over 90 min to 5200 m. The treatment group (n=20) received 50 mg sildenafil citrate three times daily. PASP was recorded by echocardiography at sea level and within 6 h, 3 days, and 1 week at 5200 m. AMS was assessed daily using the Lake Louise Consensus symptom score. On intention-to-treat analysis, there was no significant difference in PASP at 5200 m between sildenafil and placebo groups. Median AMS score on Day 2 at 5200 m was significantly higher in the sildenafil group (placebo 4.0, sildenafil 6.5; p=0.004) but there was no difference in prevalence of AMS between groups. Sildenafil administration did not affect PASP in healthy lowland subjects at 5200 m but AMS was significantly more severe on Day 2 at 5200 m with sildenafil. Our data do not support routine prophylactic use of sildenafil to reduce PASP at high altitude in healthy subjects with no history of HAPE. TRIALS REGISTRATION NUMBER: NCT00627965.

The endometrium has a remarkable capacity for efficient repair; however, factors involved remain undefined. Premenstrual progesterone withdrawal leads to increased prostaglandin (PG) production and local hypoxia. Here we determined human endometrial expression of interleukin-8 (IL-8) and the roles of PGE(2) and hypoxia in its regulation. Endometrial biopsy specimens (n = 51) were collected. Endometrial cells and explants were exposed to 100 nmol/L of PGE(2) or 0.5% O(2). The endometrial IL-8 concentration peaked during menstruation (P < 0.001) and had a significant proangiogenic effect. IL-8 was increased by PGE(2) and hypoxia in secretory but not proliferative explants, which suggests that exposure to progesterone is essential. In vitro progesterone withdrawal induced significant IL-8 up-regulation in proliferative explants primed with progestins, but only in the presence of hypoxia. Epithelial cells treated simultaneously with PGE(2) and hypoxia demonstrated synergistic increases in IL-8. Inhibition of HIF-1 by short hairpin RNA abolished hypoxic IL-8 induction, and inhibition of NF-κB by an adenoviral dominant negative inhibitor decreased PGE(2)-induced IL-8 expression (P > 0.05). Increased menstrual IL-8 is consistent with a role in repair. Progesterone withdrawal, hypoxia, and PGE(2) regulate endometrial IL-8 by acting via HIF-1 and NF-κB. Hence, progesterone withdrawal may activate two distinct pathways to initiate endometrial repair.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial.Objectives: To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved.Methods: We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF.Measurements and Main Results: Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and α-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase1. The alternative macrophage marker CD...

Several genes exhibit copy number variation (CNV), including FCGR3B which encodes the IgG receptor FcγRIIIb. Engagement of Fcγ receptors by IgG complexes may contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF).To investigate whether FCGR3B CNV is associated with susceptibility to IPF.In a case-control study we compared FCGR3B copy number in 142 patients with IPF and in 221 controls by real-time quantitative PCR using CD36 as gene copy control.Significantly increased FCGR3B:CD36 ratio was evident in the IPF cohort compared to controls (p = 0.009). Association of FCGR3B copy number with IPF susceptibility was further confirmed by a likelihood ratio statistical approach (p = 0.003). FCGR3B copy number assignment based on FCGR3B:CD36 ratios revealed significant skewing in the distribution of FCGR3B copy number between IPF patients and controls. In the IPF cohort, there was increased frequency of2 FCGR3B copies compared to controls (0.30 vs. 0.19; χ(2) = 9.27; d.f. 2; p = 0.0097). The presence of2 FCGR3B copies was associated with higher risk of IPF (p = 0.01, OR: 1.914, 95% CI: 1.17-3.12).These findings support an association of FCGR3B copy number with susceptibility to IPF and propose a novel role for Fcγ receptors in IPF disease pathogenesis.

Increased levels of inflammatory cytokines such as interleukin (IL)-1 and IL-8 occur in the bronchoalveolar lavage fluid in various lung diseases. Cytokine gene expression is controlled by transcription factors such as nuclear factor-kappaB (NF-kappaB) which can be activated by a number of stimuli including the oxidants prevent. It was hypothesized that lipopolysaccharide (LPS)-induced IL-1beta secretion may be modulated by the intracellular thiol redox status of the cells. The effect of the antioxidant compound, N-acetyl-L-cysteine (NAC), on IL-1beta release and regulation of NF-kappaB in a human myelo-monocytic cell line (THP-1) differentiated into macrophages was studied. LPS (10 microg x mL(-1)) increased IL-1beta release at 24 h compared to control levels (p

The acute respiratory distress syndrome (ARDS) represents the severe end of a spectrum of acute lung injury. Its pathogenesis classically evolves through a sequence of events: an initiating insult oftentimes distant to the lung, followed by a ‘latent period’ lasting from a few hours to a few days during which there is no clinical or radiographic evidence of lung injury and finally, in those destined to do so, progression to fulminant lung inflammation characteristic of ARDS. It is now clear however that the latent period is deceptive, for at the cellular level within the lung and indeed throughout the systemic vascular endothelium2, 3, there is an orchestrated cascade of events culminating in sustained overwhelming inflammation. Hence by the time the clinical characteristics by which we recognise ARDS have been established, significant intra-pulmonary inflammation and injury has already occurred. This may in part explain the disappointing results observed with anti-inflammatory therapy initiated in patients with established ARDS. One strategy which may resolve this dilemma is to identify at an early stage specific inflammatory mediators which are associated with ARDS progression and then target high-risk patients early in the diseasee process with specific anti-inflammatory therapy. The role inflammatory mediators in acute lung injury has recently been excellently reviewed4. Here we focus on the early at-risk period of ARDS and review possible candidates for a biological mediator which may predict ARDS progression, with particular emphasis on our experience in Edinburgh.

Aim The aim of this survey was to capture the current “state of play” with regard to ILD services, with an emphasis on idiopathic pulmonary fibrosis (IPF), in the UK. Methods The BTS Specialist Advisory Group emailed a survey to 260 clinicians. Respondents were advised to collect data prospectively for 1 month (late 2010/early 2011) before completing it. Results 120 responses were obtained, (England-96, Scotland-16, Wales-6, Northern Ireland-2), total catchment population 37.3 million, number of full-time consultants 3 (1–15). *50% of centres had a “lead” ILD consultant, 57% ran an ILD clinic and, of those centres currently without an ILD clinic, 70% anticipated setting one up in the next 5 years. For patients with all types of ILD the estimated number of new patients seen at clinic each month was 6 (1–75). *The percentage of new patients with IPF (options “ 75%”) was estimated at 18%, 36%, 27% and 18% respectively. For all ILD patients, the number of return patients seen at clinic in a month was 25 (1–300). *Only 5% of respondents were “very confident” about these figures (based on audit/registry) with 62% expressing “low confidence”. HRCT reporting was performed by “Pulmonary radiologists”/“Pulmonary radiologists with a specific ILD interest” in 48% and 36% respectively. 47% of centres did not have an ILD-multidisciplinary meeting (MDM), and for those that did, 32% held them monthly. Access to an ILD Specialist Nurse, ambulatory oxygen, pulmonary rehabilitation, palliative care and smoking cessation were 26% 93%, 81%, 93% and 97% respectively. 64% had not recruited into IPF clinical trials and 68% had no registry/database[n1]. “Triple” therapy continued to be prescribed “frequently”, prednisolone (55%), azathioprine (49%), N-acetylcysteine (45%). The reported preferred model of care for ILD patients was “local” (51%), “network” (45%) and “centre” (4%). *Median/range. Conclusions There is a wide variation in current practice, with almost half of all respondents not holding a MDM, despite BTS/ERS/ATS guidelines. Our survey has implications for the delivery of ILD care in the UK and should support the BTS in developing Quality of Care standards.

Background A significant genetic component has been described for idiopathic pulmonary fibrosis (IPF). The R131H (rs1801274) polymorphism of the IgG receptor FcγRIIa determines receptor affinity for IgG subclasses and is associated with several chronic inflammatory diseases. We investigated whether this polymorphism is associated with IPF susceptibility or progression. Methods In a case-control study, we compared the distribution of FcγRIIa R131H genotypes in 142 patients with IPF and in 218 controls using allele-specific PCR amplification. Results No differences in the frequency of FcγRIIa genotypes were evident between IPF patients and control subjects. However, significantly impaired pulmonary function at diagnosis was observed in HH compared to RR homozygotes, with evidence of more severe restriction (reduced forced vital capacity (FVC)) and lower diffusing capacity for carbon monoxide (DL CO). Similarly, increased frequency of the H131 allele was observed in patients with severe disease (DL CO < 40% predicted) (0.53 vs. 0.38; p = 0.03). Furthermore, the H131 allele was associated with progressive pulmonary fibrosis as determined by > 10% drop in FVC and/or > 15% fall in DL CO at 12 months after baseline (0.48 vs. 0.33; p = 0.023). Conclusions These findings support an association between the FcγRIIa R131H polymorphism and IPF severity and progression, supporting the involvement of immunological mechanisms in IPF pathogenesis.