Publications by authors named "Philip L Molyneaux"

76 Publications

DNA Methylome Alterations are Associated with Airway Macrophage Differentiation and Phenotype During Lung Fibrosis.

Am J Respir Crit Care Med 2021 Jul 19. Epub 2021 Jul 19.

Imperial College London, London, United Kingdom of Great Britain and Northern Ireland.

Rationale: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge of epigenetics of AMs in IPF are limited.

Methods: We undertook DNA methylation profiling using Illumina EPIC (850k) arrays in sorted AMs from Healthy (n=14) and IPF (n=30) donors. Cell-type deconvolution was performed using reference myeloid-cell DNA methylomes.

Measurements And Main Results: Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF-AMs. DNAm 'clock' analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKFB3) metabolism and importantly, DNAm status was associated with disease severity in IPF.

Conclusions: Collectively, our data identify that changes in the epigenome are associated with development and function of AMs in the IPF lung.
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http://dx.doi.org/10.1164/rccm.202101-0004OCDOI Listing
July 2021

Enhanced IL-1β Release Following NLRP3 and AIM2 Inflammasome Stimulation Is Linked to mtROS in Airway Macrophages in Pulmonary Fibrosis.

Front Immunol 2021 15;12:661811. Epub 2021 Jun 15.

Laboratory of Molecular and Cellular Pneumonology, Respiratory Medicine Department, School of Medicine, University of Crete, Heraklion, Greece.

Fibrotic Interstitial lung diseases (ILDs) are complex disorders of variable clinical behaviour. The majority of them cause significant morbidity, whilst Idiopathic Pulmonary Fibrosis (IPF) is recognised as the most relentless. NLRP3, AIM2, and NLRC4 inflammasomes are multiprotein complexes driving IL-1β release; a proinflammatory and profibrotic cytokine. Several pathogenetic factors associated with IPF are identified as inflammasome activators, including increases in mtROS and bacterial burden. Mitochondrial oxidation and alterations in bacterial burden in IPF and other ILDs may lead to augmented inflammasome activity in airway macrophages (AMs). IPF (n=14), non-IPF-ILDs (n=12) patients and healthy subjects (n=12) were prospectively recruited and AMs were isolated from bronchoalveolar lavage. IL-1β release resulting from NLRP3, AIM2 and NLRC4 inflammasomes stimulation in AMs were determined and baseline levels of mitochondrial ROS and microbial burden were also measured. Our results showed that NLRP3 was more inducible in IPF and other ILDs compared to controls. Additionally, following AIM2 activation IL-1β release was significantly higher in IPF compared to controls, whereas similar trends were observed in Non-IPF-ILDs. NLRC4 activation was similar across groups. mtROS was significantly associated with heightened NLRP3 and AIM2 activation, and mitochondrial antioxidant treatment limited inflammasome activation. Importantly, microbial burden was linked to baseline IL-1β release and and relative expression independently of mtROS. In conclusion, the above findings suggested a link between the overactivation of NLRP3 and AIM2 inflammasomes, driven by mitochondrial oxidation, in the pathogenesis of lung fibrosis while changes in the microbiota may prime the inflammasome in the lungs.
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http://dx.doi.org/10.3389/fimmu.2021.661811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248801PMC
June 2021

50-gene risk profiles in peripheral blood predict COVID-19 outcomes: A retrospective, multicenter cohort study.

EBioMedicine 2021 Jun 19;69:103439. Epub 2021 Jun 19.

Divison of Pulmonary, Critical Care & Sleep Medicine. University of South Florida, Morsani College of Medicine, Tampa, FL 33602, USA. Electronic address:

Background: COVID-19 has been associated with Interstitial Lung Disease features. The immune transcriptomic overlap between Idiopathic Pulmonary Fibrosis (IPF) and COVID-19 has not been investigated.

Methods: we analyzed blood transcript levels of 50 genes known to predict IPF mortality in three COVID-19 and two IPF cohorts. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was applied to distinguish high versus low-risk profiles in all cohorts. SAMS cutoffs derived from the COVID-19 Discovery cohort were used to predict intensive care unit (ICU) status, need for mechanical ventilation, and in-hospital mortality in the COVID-19 Validation cohort. A COVID-19 Single-cell RNA-sequencing cohort was used to identify the cellular sources of the 50-gene risk profiles. The same COVID-19 SAMS cutoffs were used to predict mortality in the IPF cohorts.

Findings: 50-gene risk profiles discriminated severe from mild COVID-19 in the Discovery cohort (P = 0·015) and predicted ICU admission, need for mechanical ventilation, and in-hospital mortality (AUC: 0·77, 0·75, and 0·74, respectively, P < 0·001) in the COVID-19 Validation cohort. In COVID-19, 50-gene expressing cells with a high-risk profile included monocytes, dendritic cells, and neutrophils, while low-risk profile-expressing cells included CD4, CD8 T lymphocytes, IgG producing plasmablasts, B cells, NK, and gamma/delta T cells. Same COVID-19 SAMS cutoffs were also predictive of mortality in the University of Chicago (HR:5·26, 95%CI:1·81-15·27, P = 0·0013) and Imperial College of London (HR:4·31, 95%CI:1·81-10·23, P = 0·0016) IPF cohorts.

Interpretation: 50-gene risk profiles in peripheral blood predict COVID-19 and IPF outcomes. The cellular sources of these gene expression changes suggest common innate and adaptive immune responses in both diseases.
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http://dx.doi.org/10.1016/j.ebiom.2021.103439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214725PMC
June 2021

Muscle stimulation in advanced idiopathic pulmonary fibrosis: a randomised placebo-controlled feasibility study.

BMJ Open 2021 06 2;11(6):e048808. Epub 2021 Jun 2.

Harefield Respiratory Research Group, Royal Brompton and Harefield Clinical Group, Guy's and St Thomas' Hospitals NHS Trust, London, UK.

Objectives: To assess the acceptability of neuromuscular electrical stimulation (NMES) of the quadriceps muscles in people with idiopathic pulmonary fibrosis (IPF) and to identify whether a future definitive trial is feasible.

Design: A randomised, parallel, two-group, participant and assessor-blinded, placebo-controlled feasibility trial with embedded qualitative interviews.

Setting: Outpatient department, Royal Brompton and Harefield Hospitals.

Participants: Twenty-two people with IPF: median (25th, 75th centiles) age 76 (74, 82) years, forced vital capacity 62 (50, 75) % predicted, 6 min walk test distance 289 (149, 360) m.

Interventions: Usual care (home-based exercise, weekly telephone support, breathlessness management leaflet) with either placebo or active NMES for 6 weeks, with follow-up at 6 and 12 weeks.

Primary Outcome Measures: Feasibility of recruitment and retention, treatment uptake and adherence, outcome assessments, participant and outcome assessor blinding and adverse events related to interventions.

Secondary Outcome Measures: Outcome measures with potential to be primary or secondary outcomes in a definitive clinical trial. In addition, purposively sampled participants were interviewed to capture their experiences and acceptability of the trial.

Results: Out of 364 people screened, 23 were recruited: 11 were allocated to each group and one was withdrawn prior to randomisation. Compared with the control group, a greater proportion of the intervention group completed the intervention, remained in the trial blinded to group allocation and experienced intervention-related adverse events. Assessor blinding was maintained. The secondary outcome measures were feasible with most missing data associated with the accelerometer. Small participant numbers precluded identification of an outcome measure suitable for a definitive trial. Qualitative findings demonstrated that trial process and active NMES were acceptable but there were concerns about the credibility of placebo NMES.

Conclusions: Primarily owing to recruitment difficulties, a definitive trial using the current protocol to evaluate NMES in people with IPF is not feasible.

Trial Registration Number: NCT03499275.
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http://dx.doi.org/10.1136/bmjopen-2021-048808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174518PMC
June 2021

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Commun Biol 2021 03 23;4(1):392. Epub 2021 Mar 23.

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10, odds ratio = 2.87, 95% confidence interval: 2.03-4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.
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http://dx.doi.org/10.1038/s42003-021-01910-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988141PMC
March 2021

Reply: A Role for Steroids in COVID-19-associated Pneumonitis at Six-Week Follow-Up?

Ann Am Thorac Soc 2021 06;18(6):1083-1084

Guy's and St. Thomas' NHS Foundation Trust London, United Kingdom.

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http://dx.doi.org/10.1513/AnnalsATS.202102-116LEDOI Listing
June 2021

Early prognostication of COVID-19 to guide hospitalisation versus outpatient monitoring using a point-of-test risk prediction score.

Thorax 2021 07 10;76(7):696-703. Epub 2021 Mar 10.

Respiratory Medicine, West Hertfordshire Hospitals NHS Trust, Watford, UK.

Introduction: Risk factors of adverse outcomes in COVID-19 are defined but stratification of mortality using non-laboratory measured scores, particularly at the time of prehospital SARS-CoV-2 testing, is lacking.

Methods: Multivariate regression with bootstrapping was used to identify independent mortality predictors in patients admitted to an acute hospital with a confirmed diagnosis of COVID-19. Predictions were externally validated in a large random sample of the ISARIC cohort (N=14 231) and a smaller cohort from Aintree (N=290).

Results: 983 patients (median age 70, IQR 53-83; in-hospital mortality 29.9%) were recruited over an 11-week study period. Through sequential modelling, a five-predictor score termed SOARS (pO2, besity, ge, espiratory rate, troke history) was developed to correlate COVID-19 severity across low, moderate and high strata of mortality risk. The score discriminated well for in-hospital death, with area under the receiver operating characteristic values of 0.82, 0.80 and 0.74 in the derivation, Aintree and ISARIC validation cohorts, respectively. Its predictive accuracy (calibration) in both external cohorts was consistently higher in patients with milder disease (SOARS 0-1), the same individuals who could be identified for safe outpatient monitoring. Prediction of a non-fatal outcome in this group was accompanied by high score sensitivity (99.2%) and negative predictive value (95.9%).

Conclusion: The SOARS score uses constitutive and readily assessed individual characteristics to predict the risk of COVID-19 death. Deployment of the score could potentially inform clinical triage in preadmission settings where expedient and reliable decision-making is key. The resurgence of SARS-CoV-2 transmission provides an opportunity to further validate and update its performance.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948158PMC
July 2021

Blood Transcriptomics Predicts Progression of Pulmonary Fibrosis and Associated Natural Killer Cells.

Am J Respir Crit Care Med 2021 Jul;204(2):197-208

Division of Pulmonary and Critical Care Medicine, The University of Virginia, Charlottesville, Virginia.

Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. To identify a predictor using short-term longitudinal changes in gene expression that forecasts future FVC decline and to characterize involved pathways and cell types. Seventy-four patients from COMET (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in IPF) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-sequencing data from healthy control subjects were used as references to characterize cell type compositions from bulk peripheral blood mononuclear RNA-sequencing data that were associated with FVC decline. The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared with a cross-sectional model. The FVC predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were downregulated and upregulated, respectively. Cellular deconvolution using single-cell RNA-sequencing data identified natural killer cells as significantly correlated with progression. Serial transcriptomic change predicts future FVC decline. An analysis of cell types involved in the progressor signature supports the novel involvement of natural killer cells in IPF progression.
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http://dx.doi.org/10.1164/rccm.202008-3093OCDOI Listing
July 2021

The microbiome in IPF: tissue is not the issue.

Thorax 2021 03;76(3):218

National Heart and Lung Institute, Imperial College London, London, UK

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http://dx.doi.org/10.1136/thoraxjnl-2020-216330DOI Listing
March 2021

Monocyte Count as a Prognostic Biomarker in Patients with Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2021 Jul;204(1):74-81

Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom.

There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count. We used pooled data from pirfenidone and IFNγ-1b trials to explore the association between monocyte count and prognosis in patients with IPF. This retrospective pooled analysis included patients (active and placebo arms) from the following four phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in FVC% predicted, ≥50 m decline in 6-minute-walk distance, or death), all-cause hospitalization, and all-cause mortality over 1 year. The relationship between monocyte count (defined as time-dependent) and outcomes was assessed using bivariate and multivariable models. This analysis included 2,067 patients stratified by monocyte count (at baseline: <0.60 × 10 cells/L [ = 1,609], 0.60 to <0.95 × 10 cells/L [ = 408], and ≥0.95 × 10 cells/L [ = 50]). In adjusted analyses, a higher proportion of patients with monocyte counts of 0.60 to <0.95 × 10 cells/L or ≥0.95 × 10 cells/L versus <0.60 × 10 cells/L experienced IPF progression ( = 0.016 and  = 0.002, respectively), all-cause hospitalization ( = 0.030 and  = 0.003, respectively), and all-cause mortality ( = 0.005 and  < 0.001, respectively) over 1 year. Change in monocyte count from baseline was not associated with any of the outcomes over 1 year and did not appear to be affected by study treatment. In patients with IPF, elevated monocyte count was associated with increased risks of IPF progression, hospitalization, and mortality. Monocyte count may provide a simple and inexpensive prognostic biomarker in IPF.
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http://dx.doi.org/10.1164/rccm.202003-0669OCDOI Listing
July 2021

Persistent Post-COVID-19 Interstitial Lung Disease. An Observational Study of Corticosteroid Treatment.

Ann Am Thorac Soc 2021 05;18(5):799-806

Department of Respiratory Medicine and.

The natural history of recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unknown. Because fibrosis with persistent physiological deficit is a previously described feature of patients recovering from similar coronaviruses, treatment represents an early opportunity to modify the disease course, potentially preventing irreversible impairment. Determine the incidence of and describe the progression of persistent inflammatory interstitial lung disease (ILD) following SARS-CoV-2 when treated with prednisolone. A structured assessment protocol screened for sequelae of SARS-CoV-2 pneumonitis. Eight hundred thirty-seven patients were assessed by telephone 4 weeks after discharge. Those with ongoing symptoms had outpatient assessment at 6 weeks. Thirty patients diagnosed with persistent interstitial lung changes at a multidisciplinary team meeting were reviewed in the interstitial lung disease service and offered treatment. These patients had persistent, nonimproving symptoms. At 4 weeks after discharge, 39% of patients reported ongoing symptoms (325/837) and were assessed. Interstitial lung disease, predominantly organizing pneumonia, with significant functional deficit was observed in 35/837 survivors (4.8%). Thirty of these patients received steroid treatment, resulting in a mean relative increase in transfer factor following treatment of 31.6% (standard deviation [SD] ± 27.6,  < 0.001), and forced vital capacity of 9.6% (SD ± 13.0,  = 0.014), with significant symptomatic and radiological improvement. Following SARS-CoV-2 pneumonitis, a cohort of patients are left with both radiological inflammatory lung disease and persistent physiological and functional deficit. Early treatment with corticosteroids was well tolerated and associated with rapid and significant improvement. These preliminary data should inform further study into the natural history and potential treatment for patients with persistent inflammatory ILD following SARS-CoV-2 infection.
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http://dx.doi.org/10.1513/AnnalsATS.202008-1002OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086530PMC
May 2021

Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression.

Respirology 2021 May 17;26(5):461-468. Epub 2020 Dec 17.

Interstitial Lung Disease Unit, Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, UK.

Background And Objective: The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury.

Methods: Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis.

Results: In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DL decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DL in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage.

Conclusion: Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.
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http://dx.doi.org/10.1111/resp.13988DOI Listing
May 2021

Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis.

Eur Respir J 2021 05 27;57(5). Epub 2021 May 27.

National Institute for Health Research Respiratory Clinical Research Facility, Royal Brompton and Harefield NHS Foundation Trust, and Fibrosis Research Group, National Heart and Lung Institute, Imperial College London, London, UK.

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 ( ) values ranging from 0.6 to 3 h and a plasma half-life ( ) 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.
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http://dx.doi.org/10.1183/13993003.02559-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156151PMC
May 2021

Itaconate controls the severity of pulmonary fibrosis.

Sci Immunol 2020 10;5(52)

National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression () is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.
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http://dx.doi.org/10.1126/sciimmunol.abc1884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116646PMC
October 2020

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Am J Respir Crit Care Med 2020 12;202(12):1656-1665

Oxford Interstitial Lung Disease Service, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18;  = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71). Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.
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http://dx.doi.org/10.1164/rccm.202007-2794OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737581PMC
December 2020

Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities.

Lancet Respir Med 2020 09;8(9):925-934

Department of Pneumology, Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany.

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice.
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http://dx.doi.org/10.1016/S2213-2600(20)30355-6DOI Listing
September 2020

The Respiratory Microbiome in Chronic Hypersensitivity Pneumonitis Is Distinct from That of Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2021 02;203(3):339-347

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease, but, to date, no study has investigated the composition of microbial communities in the lower airways in CHP. To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects. We prospectively recruited individuals with a CHP diagnosis ( = 110), individuals with an IPF diagnosis ( = 45), and control subjects ( = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways. Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both subjects with IPF and subjects with CHP included , , , and . However, in IPF, dominated, whereas the percentage of reads assigned to in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the burden was increased in CHP, and and burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.
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http://dx.doi.org/10.1164/rccm.202002-0460OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874329PMC
February 2021

Interaction between the promoter polymorphism and mucin expression: is there a difference according to ILD subtype?

Thorax 2020 10 24;75(10):901-903. Epub 2020 Jun 24.

Interstitial Lung Disease Unit, Royal Brompton and Harefield NHS Foundation Trust/ National Heart and Lung Institute, Imperial College, London, UK.

The promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in rs35705950 T-carriers is specific to IPF.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214579DOI Listing
October 2020

Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade.

Histopathology 2020 Sep 29;77(3):423-436. Epub 2020 Jun 29.

Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

Aims: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (i) externally validate the prognostic role of pleomorphic features in E-MPM and (ii) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication.

Methods And Results: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared to those without (5.4 versus 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 versus 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous.

Conclusions: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.
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http://dx.doi.org/10.1111/his.14127DOI Listing
September 2020

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor.

Respir Res 2020 Mar 26;21(1):75. Epub 2020 Mar 26.

GlaxoSmithKline Research and Development, Stevenage, UK.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF.

Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (V), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in V > 0%) of ≥80%.

Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected V at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in V > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination.

Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug.

Trial Registration: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.
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http://dx.doi.org/10.1186/s12931-020-01339-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099768PMC
March 2020

Respiratory microbiome and epithelial interactions shape immunity in the lungs.

Immunology 2020 06 14;160(2):171-182. Epub 2020 Apr 14.

Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, UK.

The airway epithelium represents a physical barrier to the external environment acting as the first line of defence against potentially harmful environmental stimuli including microbes and allergens. However, lung epithelial cells are increasingly recognized as active effectors of microbial defence, contributing to both innate and adaptive immune function in the lower respiratory tract. These cells express an ample repertoire of pattern recognition receptors with specificity for conserved microbial and host motifs. Modern molecular techniques have uncovered the complexity of the lower respiratory tract microbiome. The interaction between the microbiota and the airway epithelium is key to understanding how stable immune homeostasis is maintained. Loss of epithelial integrity following exposure to infection can result in the onset of inflammation in susceptible individuals and may culminate in lung disease. Here we discuss the current knowledge regarding the molecular and cellular mechanisms by which the pulmonary epithelium interacts with the lung microbiome in shaping immunity in the lung. Specifically, we focus on the interactions between the lung microbiome and the cells of the conducting airways in modulating immune cell regulation, and how defects in barrier structure and function may culminate in lung disease. Understanding these interactions is fundamental in the search for more effective therapies for respiratory diseases.
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http://dx.doi.org/10.1111/imm.13195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218407PMC
June 2020

Utility of Nuclear Grading System in Epithelioid Malignant Pleural Mesothelioma in Biopsy-heavy Setting: An External Validation Study of 563 Cases.

Am J Surg Pathol 2020 03;44(3):347-356

National Heart & Lung Institute, Imperial College London.

Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P<0.001 except 2-tier nuclear grade, P=0.001). In the scenario of a single- site biopsy with tissue dimension ≤10 mm, none but age (P=0.002) were independently predictive. Our data also suggested sampling 3 sites or a maximum tissue dimension of at least 20 mm from a single site is optimal for nuclear grade assessment. In conclusion our study confirmed the utility of nuclear grade in epithelioid MPM using a biopsy-heavy cohort provided the tissue sample met minimum dimensional criteria.
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http://dx.doi.org/10.1097/PAS.0000000000001416DOI Listing
March 2020

Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent.

Eur Respir J 2020 04 3;55(4). Epub 2020 Apr 3.

National Heart and Lung Institute, Imperial College London, London, UK

Increasing bacterial burden in the lower airways of patients with idiopathic pulmonary fibrosis confers an increased risk of disease progression and mortality. However, it remains unclear whether this increased bacterial burden directly influences progression of fibrosis or simply reflects the magnitude of the underlying disease extent or severity.We prospectively recruited 193 patients who underwent bronchoscopy and received a multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Quantification of the total bacterial burden in bronchoalveolar lavage fluid was performed by 16S rRNA gene qPCR. Imaging was independently evaluated by two readers assigning quantitative scores for extent, severity and topography of radiographic changes and relationship of these features with bacterial burden was assessed.Increased bacterial burden significantly associated with disease progression (HR 2.1; 95% CI 1.287-3.474; p=0.0028). Multivariate stepwise regression demonstrated no relationship between bacterial burden and radiological features or extent of disease. When specifically considering patients with definite or probable usual interstitial pneumonia there was no difference in bacterial burden between these two groups. Despite a postulated association between pleuroparenchymal fibroelastosis and clinical infection, there was no relationship between either the presence or extent of pleuroparenchymal fibroelastosis and bacterial burden.We demonstrate that bacterial burden in the lower airways is not simply secondary to the extent of the underlying architectural destruction of the lung parenchyma seen in idiopathic pulmonary fibrosis. The independent nature of this association supports a relationship with the underlying pathogenic mechanisms and highlights the urgent need for functional studies.
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http://dx.doi.org/10.1183/13993003.01519-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136009PMC
April 2020

Dynamics of human monocytes and airway macrophages during healthy aging and after transplant.

J Exp Med 2020 03;217(3)

Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.

The ontogeny of airway macrophages (AMs) in human lung and their contribution to disease are poorly mapped out. In mice, aging is associated with an increasing proportion of peripherally, as opposed to perinatally derived AMs. We sought to understand AM ontogeny in human lung during healthy aging and after transplant. We characterized monocyte/macrophage populations from the peripheral blood and airways of healthy volunteers across infancy/childhood (2-12 yr), maturity (20-50 yr), and older adulthood (>50 yr). Single-cell RNA sequencing (scRNA-seq) was performed on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. During healthy aging, the proportions of blood bronchoalveolar lavage (BAL) classical monocytes peak in adulthood and decline in older adults. scRNA-seq of BAL cells from lung transplant recipients indicates that after transplant, the majority of AMs are recipient derived. These data show that during aging, the peripheral monocyte phenotype is consistent with that found in the airways and, furthermore, that the majority of human AMs after transplant are derived from circulating monocytes.
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http://dx.doi.org/10.1084/jem.20191236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062517PMC
March 2020

Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease.

Clin Rheumatol 2020 Apr 8;39(4):1173-1179. Epub 2020 Jan 8.

Interstitial Lung Disease Unit, National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, London, SW3 6NP, UK.

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), p = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), p = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), p = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), p = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), p = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), p = 6.6 × 10). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), p = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.
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http://dx.doi.org/10.1007/s10067-019-04922-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142048PMC
April 2020

The Role of the Lung's Microbiome in the Pathogenesis and Progression of Idiopathic Pulmonary Fibrosis.

Int J Mol Sci 2019 Nov 10;20(22). Epub 2019 Nov 10.

Respiratory Disease Unit, Department of Cardiac Thoracic, Vascular Sciences and Public Health, University of Padova, Via Giustiniani 2, 35128 Paolo, Italy.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease that commonly affects older adults and is associated with the histopathological and/or radiological patterns of usual interstitial pneumonia (UIP). Despite significant advances in our understanding of disease pathobiology and natural history, what causes IPF remains unknown. A potential role for infection in the disease's pathogenesis and progression or as a trigger of acute exacerbation has long been postulated, but initial studies based on traditional culture methods have yielded inconsistent results. The recent application to IPF of culture-independent techniques for microbiological analysis has revealed previously unappreciated alterations of the lung microbiome, as well as an increased bacterial burden in the bronchoalveolar lavage (BAL) of IPF patients, although correlation does not necessarily entail causation. In addition, the lung microbiome remains only partially characterized and further research should investigate organisms other than bacteria and viruses, including fungi. The clarification of the role of the microbiome in the pathogenesis and progression of IPF may potentially allow its manipulation, providing an opportunity for targeted therapeutic intervention.
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http://dx.doi.org/10.3390/ijms20225618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888416PMC
November 2019

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2020 03;201(5):564-574

Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. We identified and replicated three new genome-wide significant ( < 5 × 10) signals of association with IPF susceptibility (associated with altered gene expression of , , and ) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility. The observation that decreased expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
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http://dx.doi.org/10.1164/rccm.201905-1017OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047454PMC
March 2020
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