Medicine › Pulmonary and Respiratory Medicine

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Works Count: 63559

Wikipedia

Description

This cluster of papers focuses on the diagnosis, management, and pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive and fatal lung disease. It covers evidence-based guidelines, cellular and molecular mechanisms of fibrosis, therapeutic translation, treatment trials with drugs like pirfenidone and nintedanib, as well as the role of myofibroblasts and epithelial-mesenchymal transition in lung fibrosis.

Keywords

Idiopathic Pulmonary Fibrosis; Fibrosis; Interstitial Lung Disease; TGF-ß; Myofibroblast; Pirfenidone; Nintedanib; Epithelial-Mesenchymal Transition; Lung Fibrosis; Bronchoalveolar Lavage

An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features

2015-07-09

Aryeh Fischer , Katerina M. Antoniou , Kevin M. Brown +7 more

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers … Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort. The “European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease” was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity. The task force proposes the term “interstitial pneumonia with autoimmune features” (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features. A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort.

View PDF Chat

An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline

2015-07-15

Ganesh Raghu , Bram Rochwerg , Yuan Zhang +7 more

Section:ChooseTop of pageAbstract <<Executive SummaryContentsOverviewIntroductionMethodsRecommendations for Speci...ConclusionsFuture DirectionsReferencesCITING ARTICLES Section:ChooseTop of pageAbstract <<Executive SummaryContentsOverviewIntroductionMethodsRecommendations for Speci...ConclusionsFuture DirectionsReferencesCITING ARTICLES

TGF-β signaling in fibrosis

2011-07-11

Anna Biernacka , Marcin Dobaczewski , Nikolaos G. Frangogiannis

Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting … Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting matrix preservation. Studies in a wide range of experimental models have demonstrated the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis. Smad-independent pathways may regulate Smad activation and, under certain conditions, may directly transduce fibrogenic signals. The profibrotic actions of TGF-β are mediated, at least in part, through induction of its downstream effector, connective tissue growth factor. In light of its essential role in the pathogenesis of fibrosis, TGF-β has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-β and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-β blockade. This minireview summarizes the role of TGF-β signaling pathways in the fibrotic response.

View PDF Chat

Cellular and molecular mechanisms of fibrosis

2007-12-27

Thomas A. Wynn

Abstract Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result … Abstract Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen‐producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial‐mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast‐like cells called fibrocytes that are derived from bone‐marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen‐associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL‐13, IL‐21, TGF‐β1), chemokines (MCP‐1, MIP‐1β), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator‐activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin–angiotensin–aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

View PDF Chat

Fibrotic disease and the TH1/TH2 paradigm

2004-07-30

Thomas A. Wynn

View PDF Chat

A CommonMUC5BPromoter Polymorphism and Pulmonary Fibrosis

2011-04-20

Max A. Seibold , Anastasia L. Wise , Marcy C. Speer +7 more

The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk.

View PDF Chat

Idiopathic pulmonary fibrosis

2011-06-30

Talmadge E. King , Annie Pardo , Moisés Selman

Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy

2001-01-16

Moisés Selman , Talmadge E. King , Annie Pardo

Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung's architecture. Although the … Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung's architecture. Although the pathogenetic mechanisms remain to be determined, the prevailing hypothesis holds that fibrosis is preceded and provoked by a chronic inflammatory process that injures the lung and modulates lung fibrogenesis, leading to the end-stage fibrotic scar. However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether inflammation is relevant to the development of the fibrotic process. Evidence suggests that inflammation does not play a pivotal role. Inflammation is not a prominent histopathologic finding, and epithelial injury in the absence of ongoing inflammation is sufficient to stimulate the development of fibrosis. In addition, the inflammatory response to a lung fibrogenic insult is not necessarily related to the fibrotic response. Clinical measurements of inflammation fail to correlate with stage or outcome, and potent anti-inflammatory therapy does not improve outcome. This review presents a growing body of evidence suggesting that idiopathic pulmonary fibrosis involves abnormal wound healing in response to multiple, microscopic sites of ongoing alveolar epithelial injury and activation associated with the formation of patchy fibroblast–myofibroblast foci, which evolve to fibrosis. Progress in understanding the fibrogenic mechanisms in the lung is likely to yield more effective therapies.

Macrophages: Master Regulators of Inflammation and Fibrosis

2010-07-21

Thomas A. Wynn , Luke Barron

Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-beta1 and … Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-beta1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro- and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master "producers" of fibrosis, this review will illustrate how macrophages function as the master "regulators" of fibrosis.

View PDF Chat

Mechanisms of fibrosis: therapeutic translation for fibrotic disease

2012-07-01

Thomas A. Wynn , Thirumalai R. Ramalingam

View PDF Chat

Idiopathic Pulmonary Fibrosis

2001-08-16

Thomas Groß , Gary W. Hunninghake

Idiopathic pulmonary fibrosis is characterized by radiographically evident interstitial infiltrates predominantly affecting the lung bases and by progressive dyspnea and worsening of pulmonary function. No therapy has been clearly shown … Idiopathic pulmonary fibrosis is characterized by radiographically evident interstitial infiltrates predominantly affecting the lung bases and by progressive dyspnea and worsening of pulmonary function. No therapy has been clearly shown to prolong survival.1 The current strict definition of idiopathic pulmonary fibrosis provides a new focus for basic and clinical research that will improve insight into the pathogenesis of this disorder and stimulate the development of novel therapies.DefinitionIdiopathic pulmonary fibrosis, also known as cryptogenic fibrosing alveolitis, is one of a family of idiopathic pneumonias sharing the clinical features of shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying . . .

Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials

2011-05-01

Paul W. Noble , Carlo Albera , Williamson Z. Bradford +7 more

A Multidimensional Index and Staging System for Idiopathic Pulmonary Fibrosis

2012-05-15

Brett Ley , Christopher J. Ryerson , Eric Vittinghoff +7 more

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an overall poor prognosis. A simple-to-use staging system for IPF may improve prognostication, help guide management, and facilitate … Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an overall poor prognosis. A simple-to-use staging system for IPF may improve prognostication, help guide management, and facilitate research. Objective: To develop a multidimensional prognostic staging system for IPF by using commonly measured clinical and physiologic variables. Design: A clinical prediction model was developed and validated by using retrospective data from 3 large, geographically distinct cohorts. Setting: Interstitial lung disease referral centers in California, Minnesota, and Italy. Patients: 228 patients with IPF at the University of California, San Francisco (derivation cohort), and 330 patients at the Mayo Clinic and Morgagni-Pierantoni Hospital (validation cohort). Measurements: The primary outcome was mortality, treating transplantation as a competing risk. Model discrimination was assessed by the c-index, and calibration was assessed by comparing predicted and observed cumulative mortality at 1, 2, and 3 years. Results: Four variables were included in the final model: gender (G), age (A), and 2 lung physiology variables (P) (FVC and Dlco). A model using continuous predictors (GAP calculator) and a simple point-scoring system (GAP index) performed similarly in derivation (c-index of 70.8 and 69.3, respectively) and validation (c-index of 69.1 and 68.7, respectively). Three stages (stages I, II, and III) were identified based on the GAP index with 1-year mortality of 6%, 16%, and 39%, respectively. The GAP models performed similarly in pooled follow-up visits (c-index ≥71.9). Limitation: Patients were drawn from academic centers and analyzed retrospectively. Conclusion: The GAP models use commonly measured clinical and physiologic variables to predict mortality in patients with IPF. Primary Funding Source: University of California, San Francisco Clinical and Translational Science Institute.

Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix

2006-08-22

Kevin K. Kim , Matthias C. Kugler , Paul J. Wolters +5 more

Mechanisms leading to fibroblast accumulation during pulmonary fibrogenesis remain unclear. Although there is in vitro evidence of lung alveolar epithelial-to-mesenchymal transition (EMT), whether EMT occurs within the lung is currently … Mechanisms leading to fibroblast accumulation during pulmonary fibrogenesis remain unclear. Although there is in vitro evidence of lung alveolar epithelial-to-mesenchymal transition (EMT), whether EMT occurs within the lung is currently unknown. Biopsies from fibrotic human lungs demonstrate epithelial cells with mesenchymal features, suggesting EMT. To more definitively test the capacity of alveolar epithelial cells for EMT, mice expressing beta-galactosidase (beta-gal) exclusively in lung epithelial cells were generated, and their fates were followed in an established model of pulmonary fibrosis, overexpression of active TGF-beta1. beta-gal-positive cells expressing mesenchymal markers accumulated within 3 weeks of in vivo TGF-beta1 expression. The increase in vimentin-positive cells within injured lungs was nearly all beta-gal-positive, indicating epithelial cells as the main source of mesenchymal expansion in this model. Ex vivo, primary alveolar epithelial cells cultured on provisional matrix components, fibronectin or fibrin, undergo robust EMT via integrin-dependent activation of endogenous latent TGF-beta1. In contrast, primary cells cultured on laminin/collagen mixtures do not activate the TGF-beta1 pathway and, if exposed to active TGF-beta1, undergo apoptosis rather than EMT. These data reveal alveolar epithelial cells as progenitors for fibroblasts in vivo and implicate the provisional extracellular matrix as a key regulator of epithelial transdifferentiation during fibrogenesis.

View PDF Chat

Simple method of estimating severity of pulmonary fibrosis on a numerical scale.

1988-04-01

T Ashcroft , Judy M. Simpson , V. Timbrell

A continuous numerical scale for determining the degree of fibrosis in lung specimens was devised for correlation with other pulmonary variables such as lung function tests or mineral burden. Grading … A continuous numerical scale for determining the degree of fibrosis in lung specimens was devised for correlation with other pulmonary variables such as lung function tests or mineral burden. Grading was scored on a scale from 0 to 8, using the average of microscope field scores. The system allows fibrosis to be measured in small samples of tissue (1 cm) which can provide a detailed description of the changes in a lung, currently not possible with most existing methods.

View PDF Chat

Integrating mechanisms of pulmonary fibrosis

2011-07-04

Thomas A. Wynn

Pulmonary fibrosis is a highly heterogeneous and lethal pathological process with limited therapeutic options. Although research on the pathogenesis of pulmonary fibrosis has frequently focused on the mechanisms that regulate … Pulmonary fibrosis is a highly heterogeneous and lethal pathological process with limited therapeutic options. Although research on the pathogenesis of pulmonary fibrosis has frequently focused on the mechanisms that regulate the proliferation, activation, and differentiation of collagen-secreting myofibroblasts, recent studies have identified new pathogenic mechanisms that are critically involved in the initiation and progression of fibrosis in a variety of settings. A more detailed and integrated understanding of the cellular and molecular mechanisms of pulmonary fibrosis could help pave the way for effective therapeutics for this devastating and complex disease.

View PDF Chat

Prednisone, Azathioprine, andN-Acetylcysteine for Pulmonary Fibrosis

2012-05-20

Ganesh Raghu , Kevin J. Anstrom , Talmadge E. King +2 more

A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown.In this … A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown.In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups -- receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo -- in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period.When approximately 50% of data had been collected (with 77 patients in the combination-therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P=0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here.Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; ClinicalTrials.gov number, NCT00650091.).

View PDF Chat

Fleischner Society: Glossary of Terms for Thoracic Imaging

2008-01-15

David M. Hansell , Alexander A. Bankier , Heber MacMahon +3 more

Members of the Fleischner Society compiled a glossary of terms for thoracic imaging that replaces previous glossaries published in 1984 and 1996 for thoracic radiography and computed tomography (CT), respectively. … Members of the Fleischner Society compiled a glossary of terms for thoracic imaging that replaces previous glossaries published in 1984 and 1996 for thoracic radiography and computed tomography (CT), respectively. The need to update the previous versions came from the recognition that new words have emerged, others have become obsolete, and the meaning of some terms has changed. Brief descriptions of some diseases are included, and pictorial examples (chest radiographs and CT scans) are provided for the majority of terms.

Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity

2005-10-01

Vincent Cottin , Hilario Nunès , Pierre‐Yves Brillet +7 more

The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper … The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper zones and diffuse parenchymal lung disease with fibrosis of the lower zones of the lungs on chest computed tomography. Patients (all smokers) included 60 males and one female, with a mean age of 65 yrs. Dyspnoea on exertion was present in all patients. Basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests were as follows (mean+/-sd): total lung capacity 88%+/-17, forced vital capacity (FVC) 88%+/-18, forced expiratory volume in one second (FEV1) 80%+/-21 (% predicted), FEV1/FVC 69%+/-13, carbon monoxide diffusion capacity of the lung 37%+/-16 (% predicted), carbon monoxide transfer coefficient 46%+/-19. Pulmonary hypertension was present in 47% of patients at diagnosis, and 55% during follow-up. Patients were followed for a mean of 2.1+/-2.8 yrs from diagnosis. Survival was 87.5% at 2 yrs and 54.6% at 5 yrs, with a median of 6.1 yrs. The presence of pulmonary hypertension at diagnosis was a critical determinant of prognosis. The authors hereby individualise the computer tomography-defined syndrome of combined pulmonary fibrosis and emphysema characterised by subnormal spirometry, severe impairment of gas exchange, high prevalence of pulmonary hypertension, and poor survival.

View PDF Chat

Clinical Course and Prediction of Survival in Idiopathic Pulmonary Fibrosis

2010-10-09

Brett Ley , Harold R. Collard , Talmadge E. King

Section:ChooseTop of pageAbstract <<CLINICAL COURSE OF IPFCAUSES OF DEATHINDIVIDUAL PREDICTORS OF ...CLINICAL PREDICTION MODEL...CHALLENGES AND FUTURE DIR...ReferencesCITING ARTICLES Section:ChooseTop of pageAbstract <<CLINICAL COURSE OF IPFCAUSES OF DEATHINDIVIDUAL PREDICTORS OF ...CLINICAL PREDICTION MODEL...CHALLENGES AND FUTURE DIR...ReferencesCITING ARTICLES

Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis

2004-08-01

Roderick J. Phillips , Marie D. Burdick , Kurt Hong +6 more

Previous reports have identified a circulating pool of CD45+ collagen I+ CXCR4+ (CD45+Col I+CXCR4+) cells, termed fibrocytes, that traffic to areas of fibrosis. No studies have demonstrated that these cells … Previous reports have identified a circulating pool of CD45+ collagen I+ CXCR4+ (CD45+Col I+CXCR4+) cells, termed fibrocytes, that traffic to areas of fibrosis. No studies have demonstrated that these cells actually contribute to fibrosis, however. Pulmonary fibrosis was originally thought to be mediated solely by resident lung fibroblasts. Here we show that a population of human CD45+Col I+CXCR4+ circulating fibrocytes migrates in response to CXCL12 and traffics to the lungs in a murine model of bleomycin-induced pulmonary fibrosis. Next, we demonstrated that murine CD45+Col I+CXCR4+ fibrocytes also traffic to the lungs in response to a bleomycin challenge. Maximal intrapulmonary recruitment of CD45+Col I+CXCR4+ fibrocytes directly correlated with increased collagen deposition in the lungs. Treatment of bleomycin-exposed animals with specific neutralizing anti-CXCL12 Ab’s inhibited intrapulmonary recruitment of CD45+Col I+CXCR4+ circulating fibrocytes and attenuated lung fibrosis. Thus, our results demonstrate, we believe for the first time, that circulating fibrocytes contribute to the pathogenesis of pulmonary fibrosis.

View PDF Chat

Incidence and Prevalence of Idiopathic Pulmonary Fibrosis

2006-06-30

Ganesh Raghu , Derek Weycker , John Edelsberg +2 more

Idiopathic pulmonary fibrosis is a chronic interstitial lung disease of unknown etiology; its epidemiology in the United States has not been well characterized.To estimate the annual incidence and prevalence of … Idiopathic pulmonary fibrosis is a chronic interstitial lung disease of unknown etiology; its epidemiology in the United States has not been well characterized.To estimate the annual incidence and prevalence of idiopathic pulmonary fibrosis in the United States.Retrospective cohort design utilizing a large health care claims database spanning the period January 1996 through December 2000.Persons with idiopathic pulmonary fibrosis were identified based on diagnosis and procedure codes. Using broad case-finding criteria, prevalence was estimated to range from 4.0 per 100,000 persons aged 18 to 34 yr to 227.2 per 100,000 among those 75 yr or older; annual incidence was estimated to range from 1.2 to 76.4 per 100,000. Using narrow case-finding criteria, prevalence ranged from 0.8 to 64.7 per 100,000 persons; comparable figures for incidence were 0.4 to 27.1 per 100,000 persons. Extrapolating these rates to the overall United States' population, prevalence was estimated to be 42.7 per 100,000 (incidence, 16.3 per 100,000) using broad criteria; with narrow criteria, prevalence was estimated to be 14.0 per 100,000 (incidence, 6.8 per 100,000).Our results suggest that idiopathic pulmonary fibrosis is probably more common in the United States than previously reported.

Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

2014-05-18

Luca Richeldi , Roland M. du Bois , Ganesh Raghu +7 more

Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced … Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis.We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period.A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

View PDF Chat

An Official American Thoracic Society Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease

2012-05-01

Keith C. Meyer , Ganesh Raghu , Robert P. Baughman +7 more

Section:ChooseTop of pageAbstract <<ContentsExecutive SummaryIntroductionMethodsBal Cellular Analyses as ...Performing, Handling, and...Bal Cellular Analysis In ...Conclusions and Future Di...Note From ATS Documents E...ReferencesCITING ARTICLES Section:ChooseTop of pageAbstract <<ContentsExecutive SummaryIntroductionMethodsBal Cellular Analyses as ...Performing, Handling, and...Bal Cellular Analysis In ...Conclusions and Future Di...Note From ATS Documents E...ReferencesCITING ARTICLES

Prognostic Significance of Histopathologic Subsets in Idiopathic Pulmonary Fibrosis

1998-01-01

Julie A. Bjoraker , Jay H. Ryu , Mark Edwin +4 more

Idiopathic pulmonary fibrosis (IPF) is a generally fatal disorder with a reported median survival of 3 to 6 yr. This has been based on relatively few studies with diagnoses inconsistently … Idiopathic pulmonary fibrosis (IPF) is a generally fatal disorder with a reported median survival of 3 to 6 yr. This has been based on relatively few studies with diagnoses inconsistently confirmed by adequate lung biopsy. Retrospective analysis of 104 patients with IPF who had open lung biopsy (OLB) at Mayo Medical Center from 1976 to 1985 was performed to establish the overall survival rate, the spectrum of histopathological subgroups and their associated prognostic significance. The study group consisted of 54 men and 50 women with a median age of 63 yr. Median survival was 3.8 yr after diagnosis by OLB with an estimated 10 yr survival of 27%. Current histopathologic review showed a heterogeneous group including usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia/fibrosis (NSIP), acute interstitial pneumonia (AIP), bronchiolitis, bronchiolitis obliterans organizing pneumonia (BOOP), and others. Median survival of the UIP group was 2.8 yr which is significantly worse (p < 0.001) than for other subgroups of chronic interstitial pneumonias. IPF includes several histopathologic subgroups with significantly different survival rates. Patients with UIP have worse survival than patients with other types of idiopathic chronic interstitial pneumonias including NSIP. Accurate histopathologic classification is essential for prognostication in patients with IPF.

Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition

2011-11-28

Jason R. Rock , Christina E. Barkauskas , Michael J. Cronce +5 more

There are currently few treatment options for pulmonary fibrosis. Innovations may come from a better understanding of the cellular origin of the characteristic fibrotic lesions. We have analyzed normal and … There are currently few treatment options for pulmonary fibrosis. Innovations may come from a better understanding of the cellular origin of the characteristic fibrotic lesions. We have analyzed normal and fibrotic mouse and human lungs by confocal microscopy to define stromal cell populations with respect to several commonly used markers. In both species, we observed unexpected heterogeneity of stromal cells. These include numerous cells with molecular and morphological characteristics of pericytes, implicated as a source of myofibroblasts in other fibrotic tissues. We used mouse genetic tools to follow the fates of specific cell types in the bleomcyin-induced model of pulmonary fibrosis. Using inducible transgenic alleles to lineage trace pericyte-like cells in the alveolar interstitium, we show that this population proliferates in fibrotic regions. However, neither these cells nor their descendants express high levels of the myofibroblast marker alpha smooth muscle actin (Acta2, aSMA). We then used a Surfactant protein C-CreER T2 knock-in allele to follow the fate of Type II alveolar cells (AEC2) in vivo. We find no evidence at the cellular or molecular level for epithelial to mesenchymal transition of labeled cells into myofibroblasts. Rather, bleomycin accelerates the previously reported conversion of AEC2 into AEC1 cells. Similarly, epithelial cells labeled with our Scgb1a1-CreER allele do not give rise to fibroblasts but generate both AEC2 and AEC1 cells in response to bleomycin-induced lung injury. Taken together, our results show a previously unappreciated heterogeneity of cell types proliferating in fibrotic lesions and exclude pericytes and two epithelial cell populations as the origin of myofibroblasts.

View PDF Chat

An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias

2013-09-15

William D. Travis , Ulrich Costabel , David M. Hansell +7 more

Section:ChooseTop of pageAbstract <<ContentsExecutive SummaryIntroductionMethodsSummary of Major Revision...General Progress in IIPs ...Important Differential Di...Progress in Specific IIPs...Rare IIPsRare Histologic PatternsUnclassifiable IIPClinical Classification o...BiomarkersReferencesCITING ARTICLES Section:ChooseTop of pageAbstract <<ContentsExecutive SummaryIntroductionMethodsSummary of Major Revision...General Progress in IIPs ...Important Differential Di...Progress in Specific IIPs...Rare IIPsRare Histologic PatternsUnclassifiable IIPClinical Classification o...BiomarkersReferencesCITING ARTICLES

View PDF Chat

Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis

2011-09-21

Luca Richeldi , Ulrich Costabel , Moisés Selman +7 more

Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in … Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity.A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).

View PDF Chat

Idiopathic Pulmonary Fibrosis

1998-04-01

Anna-Luise A. Katzenstein , Jeffrey L. Myers

Acute Exacerbations of Idiopathic Pulmonary Fibrosis

2007-06-21

Harold R. Collard , Bethany B. Moore , Kevin R. Flaherty +7 more

Section:ChooseTop of pageAbstract <<SIGNIFICANCE OF ACUTE EXA...CURRENT DIAGNOSIS AND MAN...RECOGNIZED COMPONENTS OF ...PROPOSED DEFINITION AND D...POTENTIAL ETIOLOGY AND BI...FUTURE DIRECTIONSReferencesCITING ARTICLES Section:ChooseTop of pageAbstract <<SIGNIFICANCE OF ACUTE EXA...CURRENT DIAGNOSIS AND MAN...RECOGNIZED COMPONENTS OF ...PROPOSED DEFINITION AND D...POTENTIAL ETIOLOGY AND BI...FUTURE DIRECTIONSReferencesCITING ARTICLES

View PDF Chat

An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management

2011-03-15

Ganesh Raghu , Harold R. Collard , Jim Egan +7 more

Section:ChooseTop of pageAbstract <<CONTENTSOBJECTIVEMETHODSSIGNIFICANCE OF EVIDENCE-...SUMMARY CONCLUSIONS AND T...DEFINITION AND EPIDEMIOLO...DEFINITION OF UIP PATTERNDIAGNOSISNATURAL HISTORY OF IPFSTAGING AND PROGNOSISTREATMENTTREATMENT OF SELECTED COM...PALLIATIVE CAREMONITORING THE CLINICAL C...FUTURE DIRECTIONSReferencesCITING ARTICLES Section:ChooseTop of pageAbstract <<CONTENTSOBJECTIVEMETHODSSIGNIFICANCE OF EVIDENCE-...SUMMARY CONCLUSIONS AND T...DEFINITION AND EPIDEMIOLO...DEFINITION OF UIP PATTERNDIAGNOSISNATURAL HISTORY OF IPFSTAGING AND PROGNOSISTREATMENTTREATMENT OF SELECTED COM...PALLIATIVE CAREMONITORING THE CLINICAL C...FUTURE DIRECTIONSReferencesCITING ARTICLES

View PDF Chat

A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

2014-05-18

Talmadge E. King , Williamson Z. Bradford , Socorro Castro-Bernardini +7 more

In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients … In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients.In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis.In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation.Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

View PDF Chat

TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease

2007-07-14

Brigham C. Willis , Zea Borok

Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role … Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor (TGF)-beta induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of TGF-beta and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of fibrotic lung disease. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.

American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias

2002-01-15

Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report

2016-06-14

Harold R. Collard , Christopher J. Ryerson , Tamera J. Corte +7 more

Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation … Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.

Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999

1999-01-01

Statement on sarcoidosis

Cellular senescence mediates fibrotic pulmonary disease

2017-02-23

Marissa J. Schafer , Thomas A. White , Koji Iijima +7 more

Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell … Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function.

View PDF Chat

Idiopathic pulmonary fibrosis

2017-03-30

Luca Richeldi , Harold R. Collard , Mark G. Jones

Idiopathic Pulmonary Fibrosis: Diagnosis and Treatment

2000-02-01

Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span

2017-07-10

Alexander V. Misharin , Luisa Morales‐Nebreda , Paul A. Reyfman +7 more

Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their … Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

View PDF Chat

Idiopathic Pulmonary Fibrosis

2018-05-09

David J. Lederer , Fernando J. Martínez

Idiopathic pulmonary fibrosis appears to be increasing in incidence. It requires early recognition and intervention with supportive care and pharmacologic agents to forestall its progression. Lung transplantation may be curative. Idiopathic pulmonary fibrosis appears to be increasing in incidence. It requires early recognition and intervention with supportive care and pharmacologic agents to forestall its progression. Lung transplantation may be curative.

Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline

2018-08-31

Ganesh Raghu , Martine Rémy‐Jardin , Jeffrey L. Myers +7 more

This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and … This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society.The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach.The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs.The guideline panel provided recommendations related to the diagnosis of IPF.

Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis

2018-12-15

Paul A. Reyfman , James M. Walter , Nikita Joshi +7 more

The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis … The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis.

View PDF Chat

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

2019-01-05

Jamie N. Justice , Anoop M. Nambiar , Tamar Tchkonia +7 more

BackgroundCellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. … BackgroundCellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.MethodsA two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.FindingsFourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).InterpretationOur first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases.ClinicalTrials.gov identifier: NCT02874989 (posted 2016–2018).

View PDF Chat

Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage

2019-01-04

Dvir Aran , Agnieszka Looney , Leqian Liu +7 more

View PDF Chat

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases

2019-09-29

Kevin R. Flaherty , Athol U. Wells , Vincent Cottin +7 more

Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in … Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.

View PDF Chat

Idiopathic pulmonary fibrosis

2017-10-19

Fernando J. Martínez , Harold R. Collard , Annie Pardo +6 more

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy

2020-05-16

Peter M. George , Athol U. Wells , Gisli Jenkins

In December, 2019, reports emerged from Wuhan, China, of a severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the end of April, 2020, over … In December, 2019, reports emerged from Wuhan, China, of a severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the end of April, 2020, over 3 million people had been confirmed infected, with over 1 million in the USA alone, and over 215 000 deaths. The symptoms associated with COVID-19 are diverse, ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome. The major risk factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis (IPF), namely increasing age, male sex, and comorbidities such as hypertension and diabetes. However, the role of antifibrotic therapy in patients with IPF who contract SARS-CoV-2 infection, and the scientific rationale for their continuation or cessation, is poorly defined. Furthermore, several licensed and potential antifibrotic compounds have been assessed in models of acute lung injury and viral pneumonia. Data from previous coronavirus infections such as severe acute respiratory syndrome and Middle East respiratory syndrome, as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection. Antifibrotic therapies that are available or in development could have value in preventing severe COVID-19 in patients with IPF, have the potential to treat severe COVID-19 in patients without IPF, and might have a role in preventing fibrosis after SARS-CoV-2 infection.

View PDF Chat

Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis

2020-07-08

Taylor Adams , Jonas C. Schupp , Sergio Poli +7 more

Human lung single-cell atlas reveals the complexity and diversity of aberrant cellular populations in pulmonary fibrosis. Human lung single-cell atlas reveals the complexity and diversity of aberrant cellular populations in pulmonary fibrosis.

View PDF Chat

Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline

2022-04-29

Ganesh Raghu , Martine Rémy‐Jardin , Luca Richeldi +7 more

Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary … Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results:1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.

View PDF Chat

Multidisciplinary Approach to Familial Pulmonary Fibrosis

2025-06-26

| Radiographics

Multidisciplinary Approach to Familial Pulmonary Fibrosis

2025-06-26

| Radiographics

Multidisciplinary Approach to Familial Pulmonary Fibrosis

2025-06-26

| Radiographics

Mesenchymal stem cells-derived exosomes alleviate radiation induced pulmonary fibrosis by inhibiting the protein kinase B/nuclear factor kappa B pathway

2025-06-25

Lili Wang , Mingyue Ouyang , Zunhua Yang +3 more | World Journal of Stem Cells

BACKGROUND Radiation induced pulmonary fibrosis (RIPF) is a long-term lung condition with a bleak outlook and few treatment possibilities. Mesenchymal stem cells (MSCs)-derived exosomes (MSCs-exosomes) possess tissue repair and regenerative … BACKGROUND Radiation induced pulmonary fibrosis (RIPF) is a long-term lung condition with a bleak outlook and few treatment possibilities. Mesenchymal stem cells (MSCs)-derived exosomes (MSCs-exosomes) possess tissue repair and regenerative properties, but their exact mechanisms in RIPF remain unclear. This study explores whether MSCs-exosomes can alleviate RIPF by modulating inflammation, extracellular matrix (ECM) accumulation, and epithelial-mesenchymal transition (EMT) via the protein kinase B (Akt)/nuclear factor kappa B (NF-κB) pathway. AIM To assess the therapeutic potential and mechanisms of MSCs-exosomes in RIPF. METHODS Sprague-Dawley rats were received 30 Gy X-ray radiation on the right chest to induce RIPF, while RLE-6TN and BEAS-2B cell lines were exposed to 10 Gy X-rays. Using differential centrifugation, MSCs-exosomes were isolated, and their protective effects were examined both in vivo and in vitro . Inflammatory cytokine concentrations were measured using Luminex liquid chip detection and enzyme linked immunosorbent assay. ECM and EMT-related proteins were analyzed using immunohistochemistry, western blotting, and real-time quantitative polymerase chain reaction. Western blotting and immunohistochemistry were also used to investigate the mechanisms underlying MSCs-exosomes’ effects in RIPF. RESULTS Administration of MSCs-exosomes significantly mitigated RIPF, reduced collagen deposition, and decreased levels of various inflammatory cytokines. Additionally, MSCs-exosomes prevented radiation-induced ECM accumulation and EMT. Treatment with MSCs-exosomes notably promoted cell proliferation, suppressed inflammation, and reversed ECM deposition and EMT in radiation-exposed alveolar epithelial cells. Mechanistic analysis further revealed that MSCs-exosomes exerted their anti-RIPF effects by inhibiting the Akt/NF-κB pathway, as shown in both in vivo and in vitro models. CONCLUSION MSCs-exosomes mitigate RIPF by suppressing inflammation, ECM deposition, and EMT through Akt/NF-κB inhibition, highlighting their potential as a therapeutic strategy.

Exploration of plasma factor profiles involved in tumor growth factors in non-small cell carcinoma patients with interstitial pneumonia

2025-06-25

Goushi Matama , Koichi Azuma , Akimasa Sekine +7 more | Respiratory Investigation

Targeting alveolar epithelial cell metabolism in pulmonary fibrosis: Pioneering an emerging therapeutic strategy

2025-06-25

T.S. Dai , Yidan Liang , Xin Li +5 more | Frontiers in Cell and Developmental Biology

Pulmonary fibrosis (PF) is a chronic and progressive lung disease, characterized by excessive deposition of fibrotic connective tissue within the lungs. Advances in transcriptomics, proteomics, and metabolomics have enhanced our … Pulmonary fibrosis (PF) is a chronic and progressive lung disease, characterized by excessive deposition of fibrotic connective tissue within the lungs. Advances in transcriptomics, proteomics, and metabolomics have enhanced our understanding of PF’s pathogenesis. Recent studies have indicates that metabolic abnormalities in alveolar epithelial cells (AECs) play a central role in the pathogenesis of PF. Metabolic reprogramming of AECs affects cellular senescence, endoplasmic reticulum stress, and oxidative stress in AECs, while also promoting fibrotic progression through various signaling pathways. This review focuses on therapeutic strategies targeting the metabolism of AECs. It comprehensively explores the role of metabolic pathways through glucose metabolism, lipid metabolism, and amino acid metabolism in the pathogenesis of PF, aiming to provide novel theoretical support and research perspectives for preventing and treating pulmonary fibrosis.

Updates in the Etiology and Management of Organizing Pneumonia

2025-06-25

Zohra Prasla , Shailesh Balasubramanian , Urooba Nadeem | Current Pulmonology Reports

Association of the MUC5B promoter polymorphism with idiopathic pulmonary fibrosis in a lebanese cohort

2025-06-24

Antoine Mouawad , Éliane Chouery , Alain Chebly +4 more | Frontiers in Genetics

Background and objective Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease that causes irreversible alterations in the architecture of the lung parenchyma, leading to impaired ventilation. Both environmental factors … Background and objective Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease that causes irreversible alterations in the architecture of the lung parenchyma, leading to impaired ventilation. Both environmental factors and genetic predisposition play significant roles in the development of IPF. A single nucleotide polymorphism (SNP) (rs35705950) within the promoter of the mucin 5B gene ( MUC5B) has been reported to be associated with the disease; however, no data is available from Lebanon or the Middle East. This study aims to identify the frequency of the MUC5B promoter variant among a cohort of Lebanese IPF patients, compare it to the general population and assess its association with the risk of developing the disease. Methods A total of 55 patients diagnosed with IPF, according to the ATS/ERS criteria, and 94 healthy controls were included in the study. DNA samples were extracted and genotyped for the MUC5B promoter polymorphism by Sanger sequencing. Descriptive statistics were performed on clinical characteristics. Pearson’s chi-squared and T-student tests were performed to determine statistical significance. Odds ratios quantified genetic variant associations with IPF. Results The MUC5B SNP rs35705950 was significantly more frequent in IPF patients compared to the control group, in both heterozygous and homozygous forms. Additionally, a significant association was found between the variant and susceptibility to IPF. Conclusion This study shows that the MUC5B polymorphism rs35705950 is significantly more frequent in the Lebanese IPF population compared to the control group and is associated with an increased risk of developing IPF.

Author Correction: Notch1 promotes the pericyte-myofibroblast transition in idiopathic pulmonary fibrosis through the PDGFR/ROCK1 signal pathway

2025-06-24

Yichun Wang , Qiong Chen , Junming Luo +6 more | Experimental & Molecular Medicine

Pulmonale Manifestationen der rheumatischen Erkrankungen

2025-06-24

Francesco Bonella , Georg Pongratz | Zeitschrift für Pneumologie

Zielorgan Lunge: Vielfalt der fibrotischen Lungenerkrankungen

2025-06-24

Gabriela Leuschner , Jürgen Behr | Deleted Journal

Fibrotic lung diseases are part of the large and heterogeneous group of interstitial lung diseases (ILD), which are characterized by a progressive fibrotic remodelling of alveolar lung parenchyma. Overview of … Fibrotic lung diseases are part of the large and heterogeneous group of interstitial lung diseases (ILD), which are characterized by a progressive fibrotic remodelling of alveolar lung parenchyma. Overview of the spectrum of fibrotic lung diseases. A literature search was carried out in the PubMed and MEDLINE database. The etiology of fibrotic ILD is diverse and includes inhaled exogenous noxious substances (dust, gases), infections, drug reactions, ionizing radiation and endogenous autoimmune or rare genetically determined metabolic and storage disorders; however, the etiology of some ILDs, so-called idiopathic interstitial pneumonia (IIP), is not fully understood although environmental pollution, tobacco smoke and genetic polymorphisms have been identified as risk factors. The most important and best studied representative of IIP is idiopathic pulmonary fibrosis (IPF). The diagnosis of ILD is complex and requires an interdisciplinary approach taking the clinical presentation, radiological patterns, and possibly bronchoalveolar lavage and histological findings into account. Characteristic of progressive fibrotic lung disease is progressive fibrotic tissue remodeling, which is manifested as clinical, functional and radiological deterioration and is referred to as progressive pulmonary fibrosis (PPF). Antifibrotic drugs delay the progression of IPF and PPF but are not curative. In addition to early diagnosis and preventive strategies, a better understanding of the causes of fibrotic ILD is required in order to avoid triggering noxious agents, identify dysregulated signalling pathways and develop targeted treatment.

Benefit of antifibrotic therapy initiated during acute exacerbation of interstitial lung disease: A systematic review

2025-06-24

Narat Srivali , Federica De Giacomi | Respiratory Investigation

Prognosis and prognostic factors for chronic fibrosing idiopathic interstitial pneumonias

2025-06-24

Hirotaka Nishikiori , Hirofumi Chiba | Respiratory Investigation

Hidden Markov Models Offer a Powerful Approach for Understanding Gene Regulation Mechanisms Relevant for Organ Transplantation

2025-06-24

Carlos Gonçalves , Marissa Di Napoli , David A. Schwartz +1 more | Transplantation

The human genome contains sequences of DNA enriched in cytosine-guanine dinucleotides known as CpG islands (CGIs). CGIs play a crucial role in gene regulation and expression, making them an important … The human genome contains sequences of DNA enriched in cytosine-guanine dinucleotides known as CpG islands (CGIs). CGIs play a crucial role in gene regulation and expression, making them an important target for genetic therapies. In this article, hidden Markov models (HMMs) and adaptive window techniques (AWTs) were used to identify CGIs in MUC5B and DSP genes. Both genes are associated with idiopathic pulmonary fibrosis, a progressive pulmonary disease that leads to a lung transplant. The University of California, Santa Cruz Genome Browser was used to obtain the MUC5B and DSP gene sequences and predefined CGI locations. The HMM and AWT algorithms were developed using Python version 3.11.5, and the outcomes analyzed were sensitivity, specificity, computational memory, and runtime. Both HMM and AWT exhibited high specificity; however, HMM was more accurate than AWT for both genes, 99% versus 96%, respectively. The HMM sensitivity was higher for both MUC5B and DSP genes (87% and 88%) compared with only 58% for MUC5B and 57% for DSP with AWT. Regarding computational efficiency, AWT was faster and required less memory than HMM for both genes. By accurately detecting CpG-rich regions, HMM offers a powerful approach to understanding gene regulation mechanisms. This could pave the way for more precise therapeutic interventions, enabling targeted treatment strategies for a range of genetic disorders, including idiopathic pulmonary fibrosis, improving patient outcomes, and advancing personalized medicine.

Precision medicine in rheumatoid arthritis-associated interstitial lung disease: current evidence and future directions

2025-06-23

Scott M. Matson | Current Opinion in Pulmonary Medicine

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) leads to poor survival, on average only 3-5 years from time of diagnosis. Despite its clinical impact, evidence-based treatment approaches remain limited, creating urgent … Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) leads to poor survival, on average only 3-5 years from time of diagnosis. Despite its clinical impact, evidence-based treatment approaches remain limited, creating urgent clinical uncertainty about optimal management strategies. This review examines emerging precision medicine approaches that may guide more effective, individualized treatment decisions. Current treatment paradigms based on radiologic patterns lack empirical validation, with recent evidence suggesting radiologic features poorly predict immunomodulatory response. Advances in RA joint precision medicine using synovial biopsy and RNA sequencing have identified molecular endotypes predicting differential treatment response, establishing a framework that could be applied to RA-ILD. Emerging biomarkers including leukocyte telomere length, circulating proteomics, and lung-based systems biology show promise for identifying RA-ILD molecular heterogeneity and guiding treatment selection. Progress in RA-ILD precision medicine requires multimodal approaches integrating molecular phenotyping with targeted therapeutic trials. Lessons from RA joint precision medicine suggest accessing the disease compartment directly through bronchoscopy may provide crucial information beyond peripheral biomarkers. Prospective biomarker-stratified trials are urgently needed to overcome clinical equipoise and improve outcomes for this challenging condition.

Advances and frontiers in pulmonary fibrosis and lung cancer research (2000–2024): a bibliometric analysis

2025-06-23

Yu Jiang , Jianjian Yu , Lina Fu +6 more | Frontiers in Medicine

Background Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide. In pulmonary fibrosis (PF), the incidence of lung cancer is elevated, and its prognosis … Background Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide. In pulmonary fibrosis (PF), the incidence of lung cancer is elevated, and its prognosis is worse compared to the general population. With the development of related research, the relationship between lung cancer and pulmonary fibrosis has received close attention. However, comprehensive and objective reports on this topic remain scarce. Therefore, this study aims to identify research hotspots and visualize evolving trends and collaboration networks in the field of pulmonary fibrosis and lung cancer using bibliometric and knowledge mapping tools. Methods Articles in the field of pulmonary fibrosis and lung cancer were retrieved using the Web of Science core collection subject search, and bibliometric analysis was performed in CiteSpace, VOSviewer, ChiPlot ( https://www.chiplot.online/) and Bibliometrix (R-Tool of R-Studio). Results This bibliometric analysis included 1,830 publications from 2000 to 2024, showing a steady increase over time. Collaborative network analysis identifies Japan, the United States, and China as the most influential countries, contributing the highest publications and citations. Respiratory Research is the leading journal. Bade BC is a key author, with Lung Cancer 2020: Epidemiology, Etiology, and Prevention as the most cited work. Literature and keyword analyses indicate a primary focus on diagnosis and survival, with recent shifts toward gene regulation and pulmonary inflammation. Emerging research highlights epithelial-mesenchymal transition (EMT) and chronic inflammation in lung cancer development among IPF patients. Notably, studies on immune checkpoint inhibitors (e.g., PD-1/PD-L1) have surged, reflecting a growing interest in immunotherapy. Conclusion This study is the first to employ bibliometric methods to visualize research trends and frontiers in pulmonary fibrosis and lung cancer. Our analysis reveals a shift from early studies on diagnosis and prognosis toward a growing focus on molecular mechanisms and immunotherapy. These findings offer valuable insights into emerging research directions and may serve as a reference for researchers seeking to identify key topics and potential collaborators.

Prognostic Impact of Muscle Mass in Idiopathic Interstitial Pneumonia: Analysis of Idiopathic Pulmonary Fibrosis and Other Idiopathic Interstitial Pneumonias

2025-06-23

Hiroaki Hagiwara , T Takano , Hiroaki Ogata +7 more | Research Square (Research Square)

<title>Abstract</title> Background Low skeletal muscle mass has been reported to associated with poor prognosis in patients with idiopathic pulmonary fibrosis (IPF). However, such associations have scarcely reported in idiopathic interstitial … <title>Abstract</title> Background Low skeletal muscle mass has been reported to associated with poor prognosis in patients with idiopathic pulmonary fibrosis (IPF). However, such associations have scarcely reported in idiopathic interstitial pneumonias (IIPs) other than IPF. Quantification of muscle mass obtained from chest computed tomography (CT) is used as a simple screening tool for sarcopenia in patients with respiratory diseases. However, the optimal thoracic site for muscle mass quantification is controversial. Moreover, there have been no reports investigating the association between muscle mass and acute exacerbations. This study aimed to evaluate optimal site for muscle mass quantification in chest CT to predict survival and acute exacerbation in IPF and non-IPF idiopathic interstitial pneumonias (IIPs). Methods This study included 528 patients diagnosed with IIP at 29 facilities between September 1, 2013, and April 30, 2016, following multidisciplinary discussions with prospective follow-up over a 5-year period. The cohort was divided into two groups: those with IPF and those with non-IPF IIPs. Skeletal muscle mass was quantified using the erector spinae muscle index (ESMI) and pectoralis muscle index (PMI) based on chest computed tomography (CT) at the time of enrollment. Associations between these indices at baseline and both survival and acute exacerbation were analyzed. Results In both IPF and non-IPF cohorts, Cox regression analysis revealed that patients with low ESMI had a poorer prognosis compared to those with normal ESMI, even after adjusting for age, sex, %FVC, and smoking exposure level (HR 0.62, p = 0.013; HR 0.46, p = 0.009, respectively). In contrast, no significant relationship was identified between PMI and survival. Multivariable Cox regression analysis confirmed that ESMI was an independent predictor of survival in both IPF and non-IPF patients. Additionally, acute exacerbations occurred more frequently in the low ESMI group, particularly among non-IPF patients. Conclusions The ESMI obtained from chest CT is associated with survival in not only in IPF patients but also in the non-IPF patients. The ESMI also associate with acute exacerbations in non-IPF patients.

ANCA associated pulmonary fibrosis: vasculitis or not vasculitis

2025-06-23

Helena Codes-Méndez , Diego Castillo , Patricia Moya +2 more | Current Opinion in Pulmonary Medicine

The intersection of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and interstitial lung disease (ILD) represents a complex and increasingly recognized clinical challenge. This review aims to summarize current understanding, highlight … The intersection of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and interstitial lung disease (ILD) represents a complex and increasingly recognized clinical challenge. This review aims to summarize current understanding, highlight diagnostic and therapeutic approaches, and identify key gaps in the literature regarding ANCA-associated ILD. ANCA positivity-particularly MPO-ANCA- is increasingly identified in patients with fibrotic ILD, even in the absence of systemic vasculitis. This overlap raises questions about disease classification and management, especially as radiologic patterns such as usual interstitial pneumonia (UIP) appear to predict prognosis. Immunosuppressive therapy remains the mainstay of treatment, though its role varies depending on the presence of systemic features and lung fibrosis. Emerging biomarkers, and the potential role of antifibrotic agents offer promising avenues for improved monitoring and therapy. ANCA-ILD represents a heterogeneous and underexplored disease spectrum that challenges existing classification systems. A multidisciplinary approach is critical, and prospective studies are urgently needed to redefine diagnostic criteria and guide treatment strategies in order to improve clinical outcomes.

Predictive Value of Circulating Pro-Fibrotic Cytokines for Progression in Idiopathic Pulmonary Fibrosis and Progressive Pulmonary Fibrosis (PPF): A Systematic Review and Meta-Analysis

2025-06-23

Yolanda Julia Perel Putri , Indi Esha Siregar , Dewi Wijaya | Bioscientia Medicina Journal of Biomedicine and Translational Research

Background: The clinical trajectory of patients with idiopathic pulmonary fibrosis (IPF) and the broader phenotype of progressive pulmonary fibrosis (PPF) is highly variable. Current prognostic models lack precision, highlighting an … Background: The clinical trajectory of patients with idiopathic pulmonary fibrosis (IPF) and the broader phenotype of progressive pulmonary fibrosis (PPF) is highly variable. Current prognostic models lack precision, highlighting an urgent need for reliable biomarkers. Circulating pro-fibrotic cytokines are implicated in fibrogenesis, but their individual predictive utility for disease progression remains debated. This systematic review and meta-analysis were conducted to synthesize the available evidence and quantify the predictive value of key circulating pro-fibrotic cytokines for disease progression in patients with IPF and PPF. Methods: A systematic literature search was performed in PubMed, Embase, and Scopus databases for studies published between January 1st, 2014, and December 31st, 2024. We included longitudinal cohort studies that evaluated the association between baseline circulating levels of Transforming Growth Factor-beta 1 (TGF-β1), Chemokine Ligand 18 (CCL18), or Interleukin-6 (IL-6) and a composite endpoint of disease progression (all-cause mortality, lung transplantation, or a significant decline in Forced Vital Capacity [FVC]). Hazard Ratios (HRs) and their 95% Confidence Intervals (CIs) were extracted. A random-effects model was used to pool the data. Heterogeneity was assessed using the I² statistic, and publication bias was evaluated with funnel plots and Egger’s test. Results: The search yielded 1,842 citations, from which seven studies comprising a total of 1,158 patients met the inclusion criteria. Elevated baseline levels of all three cytokines were significantly associated with an increased risk of disease progression. The pooled HR for TGF-β1 (4 studies, 650 patients) was 2.15 (95% CI: 1.55-2.98, p < 0.001), with moderate heterogeneity (I² = 55%). For CCL18 (5 studies, 812 patients), the pooled HR was 1.98 (95% CI: 1.41-2.78, p < 0.001), with substantial heterogeneity (I² = 68%). For IL-6 (3 studies, 515 patients), the pooled HR was 2.41 (95% CI: 1.78-3.26, p < 0.001), with low heterogeneity (I² = 21%). Subgroup analysis suggested a consistent predictive effect across both IPF and non-IPF PPF cohorts. Conclusion: This meta-analysis provides robust evidence that elevated circulating levels of TGF-β1, CCL18, and IL-6 are potent and independent predictors of disease progression in patients with IPF and PPF. These biomarkers hold significant promise for enhancing patient risk stratification, improving prognostic accuracy, and guiding personalized therapeutic decisions in clinical practice.

Endotypes and Phenotypes in ILD: Is It Time to Reclassify ILD by Risk Stratification?

2025-06-23

Francesco Amati , Anna Stainer , Stefano Aliberti | Biomedicines

Interstitial lung diseases (ILD) comprise a heterogeneous group of disorders that present significant challenges in both diagnosis and management due to their varied nature, which encompasses different degrees of inflammation … Interstitial lung diseases (ILD) comprise a heterogeneous group of disorders that present significant challenges in both diagnosis and management due to their varied nature, which encompasses different degrees of inflammation and fibrosis affecting lung tissue [...]

Surgical pathology of diffuse parenchymal lung disease in patients with polymyalgia rheumatica

2025-06-22

Suhashini Ganapaty , Elena Cavazzi , Peter Manchen +5 more | Histopathology

Aims Polymyalgia rheumatica (PMR) is a chronic autoimmune disorder that mainly affects older adults. Pulmonary disease in PMR is rare but may be under‐recognized and pathological descriptions thereof are few. … Aims Polymyalgia rheumatica (PMR) is a chronic autoimmune disorder that mainly affects older adults. Pulmonary disease in PMR is rare but may be under‐recognized and pathological descriptions thereof are few. We aimed to characterize diffuse parenchymal lung disease (DPLD) in PMR. Methods and results Institutional archives were searched for patients having PMR and DPLD with lung tissue sampling. After excluding cases with infection, concomitant rheumatoid arthritis, or smoking‐related DPLD only, 11 patients (9 women, median age 75 years) were enrolled. Clinical history and pathology slides were reviewed. One of the 11 patients (9%) had concomitant giant cell arteritis; the remaining patients had no other rheumatological diseases. All had been treated for PMR with immunosuppression, and most presented years later (median 6 years) with non‐specific respiratory symptoms. Radiographically, bilateral ground‐glass opacities and reticulation were typical and were usually lower lobe predominant. Histologically, fibrosis was seen in 8 of 11 (73%) patients and was unclassifiable in four; non‐specific interstitial pneumonia was encountered in three patients, and usual interstitial pneumonia was seen in only one case. Evidence of acute lung injury occurred in 9 (82%) patients, including three with acute lung injury only, usually manifesting as organizing pneumonia. Diffuse alveolar haemorrhage was seen in four cases (29%), including two patients with haemoptysis and capillaritis. Conclusions Our data corroborate prior reports of clinically significant DPLD in some patients with PMR. Histopathological findings mirror other rheumatological disorders and include diffuse alveolar haemorrhage with capillaritis. Additional studies are warranted to clarify the association between PMR and DPLD.

PNEUMONITIS AS A COMPLICATION OF IMMUNOTHERAPY OF ONCOLOGICAL DISEASES. DIFFICULTIES IN DIAGNOSIS AND TREATMENT

2025-06-22

Yuliia S. Chizhova , V. D. Fedotov , Elena M. Zakharova | Journal of clinical practice

Pneumonitis is one of the complications of cancer immunotherapy. Despite its low incidence, it has a significant impact not only on the quality of life of patients, but also on … Pneumonitis is one of the complications of cancer immunotherapy. Despite its low incidence, it has a significant impact not only on the quality of life of patients, but also on mortality. Many foreign and domestic studies have been conducted to identify and treat pneumonitis, but most of them are narrow in nature. Due to the fact that immunotherapy is becoming increasingly popular, the number of complications will also increase. Since patients are observed not only in oncology institutions, there is a need for information for doctors of different profiles. And since pneumonitis is a life-threatening complication, it is very important to maintain a high index of suspicion in order to identify it at an early stage and prescribe treatment. In our article, we have combined and systematized data from different sources, focusing on diagnostics and therapy.

Prospects of pirfenidone use in idiopathic pulmonary fibrosis and progressive pulmonary fibrosis

2025-06-22

Н. В. Трушенко , Iuliia A. Levina , B. B. Lavginova +2 more | Meditsinskiy sovet = Medical Council

Both idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are characterized by steady progression, dismal prognosis and high mortality. Antifibrotic therapies such as pirfenidone and nintedanib slow the decline … Both idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are characterized by steady progression, dismal prognosis and high mortality. Antifibrotic therapies such as pirfenidone and nintedanib slow the decline in lung function and improve patient survival, serving as the cornerstone of treatment for IPF. The use of antifibrotics in PPF has been actively explored in recent years. Pirfenidone, with its antifibrotic, anti-inflammatory, and antioxidant properties, inhibits key pathways of fibrogenesis, including TGF-β-mediated mechanisms. This review presents current data on the use of pirfenidone in IPF and PPF, including hypersensitivity pneumonitis, silicosis, and interstitial lung disease associated with connective tissue diseases. The paper reviews the mechanisms of action of pirfenidone, its evidence base (including the results of the pivotal CAPACITY, ASCEND and RELIEF clinical trials) as well as data from real-world clinical practice confirming that pirfenidone slows disease progression and decline in pulmonary function parameters in both IPF and PPF. In a comparative evaluation of pirfenidone and nintedanib, both drugs demonstrate comparable efficacy, but pirfenidone has a more predictable safety profile, with dose-related gastrointestinal disturbances and photosensitization as the most common adverse events. Serious side effects are rarely observed, making pirfenidone a relatively safe treatment option. New therapeutic strategies such as combination with nintedanib, low dose and inhaled forms of the drug are emphasized. Special attention is given to treatment optimization, considering pirfenidone’s safety profile and individual patient characteristics. The prospects for further applications of pirfenidone across different PPF subtypes are discussed.

Potential of bronchoalveolar lavage in diagnostics of progressive pulmonary fibrosis

2025-06-22

Е. В. Болотова , Yu. G. Yurkova , И. В. Гилевич +1 more | Meditsinskiy sovet = Medical Council

Introduction. Progressive pulmonary fibrosis (PPF) represents а poor prognosis in patients with interstitial lung diseases, including hypersensitivity pneumonitis (HP). Currently, along with common functional and radiological diagnostic criteria for PPF, … Introduction. Progressive pulmonary fibrosis (PPF) represents а poor prognosis in patients with interstitial lung diseases, including hypersensitivity pneumonitis (HP). Currently, along with common functional and radiological diagnostic criteria for PPF, an active search for laboratory biomarkers of PPF is underway. Aim. To study of the dynamic of metalloproteinase levels (MMP-1, MMP-7, MMP-9), monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) in bronchoalveolar lavage fluid (BAL) and their relationship with IPF criteria in patients with IPF and GP. Materials and methods. The study included 62 patients with ILD over 18 years old, the diagnosis of ILD was established based on the diagnostic criteria of the American Thoracic Society (2022). The levels of markers in bronchoalveolar lavage fluid were determined using Vector-Best kits (Russia) for quantitative determination of MCP-1 and VEGF levels and RayBiotech kits (USA) for determining the level of MMP-1, MMP-7, MMP-9. The study was conducted on a Hydro Flex enzyme immunoassay analyzer (TECAN, Austria). Statistical data processing was performed using the Statistica 10.0 program. Results. Baseline levels of MCP-1, VEGF, MMP-1, MMP-7, MMP-9 in BAL fluid were higher in patients with IPF and PLF in GP compared to patients with GP without signs of PLF. When studying the levels of MMP-7 and VEGF, a reliable association was found between an increase in these biomarkers and a decrease in FVC ≥ 5% and DLCO ≥ 10% of the predicted value within 1 year. Conclusion. Increased levels of MMP-7 and MCP-1 in BAL fluid have an inverse correlation with the dynamics of FVC and DLCO indicators during the year, which corresponds to the FVC criterion.

Cell‐Surface <scp>LAMP1</scp> is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis

2025-06-22

Gabriel Meca‐Laguna , Michael Qiu , Yafei Hou +6 more | Aging Cell

ABSTRACT The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age‐related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases … ABSTRACT The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age‐related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that Lysosomal‐Associated Membrane Protein 1 (LAMP1) is a membrane‐specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1 + cells express high levels of the prototypical senescence markers p16, p21, Glb1, and have low Lmnb1 expression as compared to Lamp1 − cells. The percentage of Lamp1 + cells is increased with age and in mice with fibrotic lungs due to bleomycin (BLM) instillation. The RNA‐Sequencing analysis of the Lamp1‐enriched populations in sham and BLM mice lung tissue revealed enrichment of several senescence‐related genes in both groups when compared to the SenMayo gene set derived from transcriptomic profiling of senescence markers in Mayo Clinic research datasets. Finally, we use a dual antibody‐drug conjugate (ADC) strategy to eliminate SEN in cell culture assay.

Pulmonary fibrosis: New horizons and clinical solutions: A review II Expert Council “Idiopathic pulmonary fibrosis and progressive pulmonary fibroses. Real Practice” Symposium Review October 26, 2024, Sochi, Russia

2025-06-21

С. Н. Авдеев , S. Yu. Chikina , Н. В. Трушенко +1 more | Consilium Medicum

This review summarizes key materials from Symposium II of the Expert Council on idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis, held on October 26, 2024, in Sochi. It highlights … This review summarizes key materials from Symposium II of the Expert Council on idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis, held on October 26, 2024, in Sochi. It highlights recent scientific advances in understanding the pathogenesis of IPF, including genetic factors and the role of fibrosenescence. Discussed are the updated clinical guidelines from the European Respiratory Society (ERS), American Thoracic Society (ATS), Japanese Respiratory Society (JRS), and Asociación Latinoamericana del Thorax (ALAT) (2022) on diagnosis, emphasizing the value of transbronchial lung cryobiopsy and high-resolution computed tomography (HRCT) patterns. Special attention is given to novel therapeutic approaches: antifibrotic drugs (nintedanib, pirfenidone), inhaled formulations, and promising agents in clinical trial phases. Research findings on the prognostic significance of symptoms (cough, crackles) and the efficacy of bioequivalent drugs are reviewed. Data from the Russian IPF patient registry underscore the importance of standardized diagnostics and monitoring. The material includes a clinical case analysis demonstrating long-term pirfenidone therapy. This review is intended for pulmonologists, rheumatologists, and specialists in interstitial lung diseases.

Combinational Therapy of Mesenchymal Stem Cells and Metformin in Bleomycin-Induced Idiopathic Pulmonary Fibrosis in Rat Model

2025-06-21

Nourhan Hassan , Mariam N Elbyoume , Muhammad Taha +7 more | Applied Biochemistry and Biotechnology

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and severe lung disease characterized by the buildup of interstitial fibrosis, where excessive collagen accumulates, leading to airway obstruction. This condition is … Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and severe lung disease characterized by the buildup of interstitial fibrosis, where excessive collagen accumulates, leading to airway obstruction. This condition is initiated by the abnormal proliferation of alveolar type II (AT2) cells. Metformin, an established antidiabetic drug, has gained attention for its repurposed use as an anti-fibrotic agent. Meanwhile, adipose-derived mesenchymal stem cells (ADMSCs) exhibit potent anti-inflammatory and regenerative properties, and they have been shown to reduce collagen deposition. In this study, we hypothesize that the combination of metformin and ADMSCs can synergistically alleviate IPF and promote healthy lung tissue regeneration in a rat model. The goal is to evaluate the safety and efficacy of this approach at multiple levels; biochemical, molecular, histopathological, and histochemical. To induce IPF, Wistar albino rats received a single intratracheal dose of bleomycin (5 mg/kg body weight). The therapeutic phase involved treatment with either metformin or ADMSCs or a combination of both. Metformin was administered intraperitoneally (65 mg/kg body weight) every other day, while ADMSCs were delivered intravenously (1 × 10⁶ cells/0.5 ml DMEM/rat) through the tail vein. Our results demonstrated the effectiveness of combinational therapy, especially in mitigating oxidative stress. This was evidenced by the restoration of oxidative stress biomarkers, malondialdehyde (MDA), and catalase (CAT), as well as the regulation of collagenase type IV (MMP9), bovine serum albumin (BSA), and total protein levels in lung tissues. Moreover, the therapy modulated the expression of key inflammatory and fibrotic genes, including the pro-fibrotic marker TGF-β1, proinflammatory cytokine IL-6, and anti-inflammatory cytokine IL-10. Histopathological and histochemical analyses further supported the therapeutic benefits, showing significant recovery from bleomycin-induced fibrosis in rats treated with either the single or combined therapy. The findings suggest that this combinational approach could be a promising strategy for IPF treatment by simultaneously reducing inflammation, oxidative stress, and fibrosis while promoting tissue regeneration. Graphical Abstract

Concizumab/Nonacog-alfa

2025-06-21

| Reactions Weekly

Features of the clinical picture and quality of life in patients with idiopathic pulmonary fibrosis and hypersensitivity pneumonitis

2025-06-21

Olga Suvorova , Н. В. Трушенко , B. B. Lavginova +3 more | Consilium Medicum

Background. Idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP) are interstitial lung diseases with similar symptoms: dyspnea and cough, which determine disease severity and serve as prognostic markers. Aim. To … Background. Idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP) are interstitial lung diseases with similar symptoms: dyspnea and cough, which determine disease severity and serve as prognostic markers. Aim. To compare clinical and functional characteristics and their dynamics in patients with IPF and different HP phenotypes, and to assess the relationship between symptoms and objective test results. Materials and methods. A longitudinal observational study included 153 patients (48 with IPF, 105 with HP, including 72 fibrotic HP [fHP], of whom 32 had a UIP pattern). Demographic, anamnestic, and functional parameters (spirometry, body plethysmography, DLco) were analyzed. Dyspnea (mMRC scale), cough (VAS and LCQ questionnaire), 6MWT results, HRCT changes, and echocardiographic signs of right heart dysfunction were assessed at baseline and after 12 months. Statistical analysis included nonparametric tests, Spearman correlation, and multiple linear regression to evaluate the impact of parameters on dyspnea and cough. Results. Patients with fHP and fHP+UIP did not significantly differ from IPF patients in dyspnea severity (mMRC), cough intensity (VAS), or functional parameters. Mortality and disease progression were comparable between IPF, fHP, and fHP+UIP groups. Dyspnea severity correlated with GAP scores, 6MWT distance, SpO2 at baseline and end of 6MWT, presence of fibrosis on HRCT, functional parameters (DLco, CPI, etc.), and Charlson Comorbidity Index. Regression analysis showed that end-exercise SpO2 and pulmonary fibrosis had the greatest impact on dyspnea. Cough correlated with fibrosis, dyspnea (mMRC), and functional parameters (FVC, FEV1, CPI). FEV1 and pulmonary fibrosis were the most significant predictors of cough severity. Conclusion. Patients with fHP, particularly those with a UIP pattern, have comparable functional impairment and clinical manifestations to IPF patients. Dyspnea and cough are closely associated with exertional desaturation, functional parameters, and pulmonary fibrosis on HRCT, which should be considered when evaluating HP and IPF.

Correction: Cheng et al. NICEFIT—A Prospective, Non-Interventional, and Multicentric Study for the Management of Idiopathic Pulmonary Fibrosis with Antifibrotic Therapy in Taiwan. Biomedicines 2022, 10, 2362

2025-06-20

Shih-Lung Cheng , Chau‐Chyun Sheu , Chih‐Feng Chian +7 more | Biomedicines

We would like to identify and amend errors in a previously published paper [...] We would like to identify and amend errors in a previously published paper [...]

PMFF-Net: A deep learning-based image classification model for UIP, NSIP, and OP

2025-06-20

Mingwei Xu , Zhenghua Zhang , Xiao Wang +4 more | Computers in Biology and Medicine

High-resolution computed tomography (HRCT) is helpful for diagnosing interstitial lung diseases (ILD), but it largely depends on the experience of physicians. Herein, our study aims to develop a deep-learning-based classification … High-resolution computed tomography (HRCT) is helpful for diagnosing interstitial lung diseases (ILD), but it largely depends on the experience of physicians. Herein, our study aims to develop a deep-learning-based classification model to differentiate the three common types of ILD, so as to provide a reference to help physicians make the diagnosis and improve the accuracy of ILD diagnosis. Patients were selected from four tertiary Grade A hospitals in Kunming based on inclusion and exclusion criteria. HRCT scans of 130 patients were included. The imaging manifestations were usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), and organizing pneumonia (OP). Additionally, 50 chest HRCT cases without imaging abnormalities during the same period were selected.Construct a data set. Conduct the training, validation, and testing of the Parallel Multi-scale Feature Fusion Network (PMFF-Net) deep learning model. Utilize Python software to generate data and charts pertaining to model performance. Assess the model's accuracy, precision, recall, and F1-score, and juxtapose its diagnostic efficacy against that of physicians across various hospital levels, with differing levels of seniority, and from various departments. The PMFF -Net deep learning model is capable of classifying imaging types such as UIP, NSIP, and OP, as well as normal imaging. In a mere 105 s, it makes the diagnosis for 18 HRCT images with a diagnostic accuracy of 92.84 %, precision of 91.88 %, recall of 91.95 %, and an F1 score of 0.9171. The diagnostic accuracy of senior radiologists (83.33 %) and pulmonologists (77.77 %) from tertiary hospitals is higher than that of internists from secondary hospitals (33.33 %). Meanwhile, the diagnostic accuracy of middle-aged radiologists (61.11 %) and pulmonologists (66.66 %) are higher than junior radiologists (38.88 %) and pulmonologists (44.44 %) in tertiary hospitals, whereas junior and middle-aged internists at secondary hospitals were unable to complete the tests. This study found that the PMFF-Net model can effectively classify UIP, NSIP, OP imaging types, and normal imaging, which can help doctors of different hospital levels and departments make clinical decisions quickly and effectively.

Antifibrotic agents in progressive pulmonary fibrosis and non-progressive pulmonary fibrosis of fibrotic hypersensitivity pneumonitis

2025-06-20

Taichi Kaneko , Ryo Okuda , Tamiko Takemura +5 more | Respiratory Investigation

Pulmonary function test abnormalities in patients with rheumatoid arthritis: A single centre study

2025-06-20

Udari Egodage , Nuwan Darshana , Sharmini Gunawardena +3 more | Galle Medical Journal

Introduction: Pulmonary diseases are common extra-articular manifestations of rheumatoid arthritis (RA) and account for a high disease-related mortality. Pulmonary function tests (PFTs) are considered as one of the cost-effective options … Introduction: Pulmonary diseases are common extra-articular manifestations of rheumatoid arthritis (RA) and account for a high disease-related mortality. Pulmonary function tests (PFTs) are considered as one of the cost-effective options for the early identification of pulmonary involvement in RA. The objective of this study was to assess the prevalence of PFT abnormalities and its associated factors among diagnosed patients with RA visiting a tertiary care hospital in Sri Lanka.Methods: A cross-sectional study was performed recruiting 42 consecutive RA patients attending the rheumatology clinic of Teaching Hospital Karapitiya, Galle, Sri Lanka (THK) in year 2018-2019. Data were collected using an interviewer-administered questionnaire. Lung functions were measured using spirometry. Mann-Whitney U test, the Spearman rank-order correlation coefficient and the Kruskal Wallis H test at 0.05 significance level were used to identify associations between variables.Results: Out of all the patients (N = 42), 57.1% showed abnormal PFT results. Among them obstructive defect was noted in 16.6%, small airway defect in 37.5% and pure restrictive defect in 45.9%. No patients with combined restrictive and obstructive diseases were detected. A statistically significant association of forced vital capacity (FVC) with the presence of respiratory symptoms (p = 0.02) was detected. Statistically significant negative correlations were reported between peak expiratory rate (PFR) and age (rs = -0.371, p = 0.01) and PFR and disease activity (rs = -0.393, p = 0.01). Age, disease duration, disease severity and presence of respiratory symptoms showed no association with types of respiratory abnormalities.Conclusions: PFT abnormalities were detected in considerable proportion of RA patients. PFTs should be performed in patients with RA, irrespective of the duration and the severity of disease or respiratory symptoms.

Construction of the predictive model for idiopathic pulmonary fibrosis: Based on endoplasmic reticulum stress and cuproptosis related genes

2025-06-20

Xiao-Xing Cai , Yaqi Yang | Deleted Journal

Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options. This study aimed to construct a predictive model for IPF based on genes related to … Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options. This study aimed to construct a predictive model for IPF based on genes related to endoplasmic reticulum (ER) stress and cuproptosis, two pathophysiological processes implicated in IPF, to improve early diagnosis and understand underlying molecular mechanisms. Methods: Two public gene expression datasets (GSE33566 and GSE38958) were used to identify differentially expressed genes (DEGs) associated with ER stress and cuproptosis. Consensus clustering was applied to define molecular subtypes of IPF. Functional enrichment analysis was conducted via gene set variation analysis (GSVA). Weighted gene co-expression network analysis (WGCNA) was performed to identify key gene modules. Multiple machine learning models, including Random Forest (RF), were constructed and evaluated to develop a robust diagnostic signature. A nomogram was created to visualize risk prediction, and the relationship between model genes and pulmonary function (DLCO) was assessed. Results: A total of 537 DEGs related to ER stress and cuproptosis were identified in IPF. Two molecular subtypes of IPF showed distinct pathway enrichment and gene expression profiles. WGCNA revealed 56 hub genes, and the RF model based on five key genes (eukaryotic translation elongation factor 1 gamma (EEF1G), actin binding LIM protein 1 (ABLIM1), Kruppel like factor 12 (KLF12), zinc finger protein 573 (ZNF573), ras homolog family member H (RHOH)) achieved strong diagnostic performance (AUC = 0.829 in training; 0.700 in external validation). Of these, four genes correlated positively with DLCO, suggesting clinical relevance. Conclusion: This study demonstrates that integrating ER stress and cuproptosis gene signatures can effectively distinguish IPF patients. The findings offer novel insights into IPF pathogenesis and highlight potential biomarkers for early detection and personalized therapy.

Risk factors for the onset of pneumothorax in idiopathic pulmonary fibrosis

2025-06-20

Ryoju Sato , Machiko Arita , Hiroshi Takahashi +4 more | Respiratory Investigation

Safety of cryobiopsy for peripheral pulmonary lesions in older people

2025-06-20

Mika Iwasaki , Keigo Uchimura , Hideaki Furuse +3 more | Respiratory Investigation

Making Sense of Dyspnea in Interstitial Lung Disease

2025-06-20

Yet H. Khor | Annals of the American Thoracic Society

Epigenome-Wide Analysis Identifies Pollution-Sensitive Loci in Fibrotic Interstitial Lung Disease

2025-06-20

G.C. Goobie , Najmeh Assadinia , Chen Xi Yang +7 more | American Journal of Respiratory and Critical Care Medicine

Particulate matter <=2.5um (PM2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). To determine whether PM2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD. Retrospective two-cohort study applying … Particulate matter <=2.5um (PM2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). To determine whether PM2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD. Retrospective two-cohort study applying satellite-derived PM2.5 and constituent exposure matching to the residential location of patients with fILD. Robust linear regressions evaluated cohort-specific epigenome-wide differential blood DNA methylation with increasing pollutant exposures (Illumina MethylationEPIC BeadChip). Cox and linear regressions evaluated associations of cytosine-phosphate-guanine (CpG) loci with transplant-free survival and lung function. Wilcoxon test evaluated cartilage-associated protein (CRTAP) levels in fILD and control lungs. The University of Pittsburgh (UPitt) cohort (n=306) had 5-year median PM2.5 exposures of 12.1ug/m3 compared with 5.1ug/m3 in the University of British Columbia (UBC) cohort (n=170). Higher pollutant exposures in the UPitt cohort were associated with lower methylation at cg25354716, annotated to CRTAP, a critical extracellular matrix remodeling enzyme. Higher exposures in the UBC cohort were associated with higher methylation at cg01019301, annotated to TLN2 (talin-2), a cytoskeletal protein involved in fibroblast migration. A 10% increase in cg25354716 methylation was associated with a hazard ratio (HR) of 0.81 for death or lung transplantation in the meta-analyzed cohorts (95%CI 0.69-0.96, p=0.01), whereas the same change in cg01019301 was associated with a HR of 1.36 (95%CI 1.07-1.74, p=0.01). CRTAP protein was more abundant in lungs from patients with fILD compared with donor controls (p<0.001). PM2.5 is associated with altered blood DNA methylation in fILD. This work identifies novel pollution-sensitive targets that hold potential for therapeutic modulation in fILD.

Fibroblast activation and heterogeneity in fibrotic disease

2025-06-19

Xiaoyao Zhang , Yuxi Zhang , Youhua Liu | Nature Reviews Nephrology

Integrins and pulmonary fibrosis: Pathogenic roles and therapeutic opportunities

2025-06-19

Zhangyang Bi , Guodong Zang , Xiaodong Wang +2 more | Biomolecules and Biomedicine

Characterized by the formation of fibrotic scars, pulmonary fibrosis (PF) involves a complex pathogenesis, limited treatment options, and a high mortality rate. Integrins—heterodimeric transmembrane proteins composed of α and β … Characterized by the formation of fibrotic scars, pulmonary fibrosis (PF) involves a complex pathogenesis, limited treatment options, and a high mortality rate. Integrins—heterodimeric transmembrane proteins composed of α and β subunits—mediate extracellular matrix remodeling and regulate the physiological functions of epithelial, mesenchymal, and immune cells through "inside-out" and "outside-in" signaling pathways. These molecules play a critical role in the initiation and progression of PF. Due to their central regulatory functions, a range of integrin-targeted therapies has been developed. However, the complex pathophysiology of PF and the structural diversity of integrins pose significant challenges to targeted treatment. In this study, we systematically delineated the signaling networks mediated by the full spectrum of integrin family members and uncovered the molecular mechanisms by which they contribute to PF through immunoregulatory pathways. We also reviewed the development of integrin-based therapies from preclinical studies to clinical trials and discussed current priorities in clinical, basic, and translational research. These insights may provide new perspectives for the diagnosis and treatment of PF.

Basement membrane repair response biomarker PRO-C4 predicts progression in idiopathic pulmonary fibrosis: analysis of the PFBIO and PROFILE cohorts

2025-06-19

Jannie Marie Bülow Sand , Peder Frederiksen , Alison E. John +7 more | Thorax

Background Idiopathic pulmonary fibrosis (IPF) is characterised by damage to the epithelial layer, closely associated with the alveolar basement membrane (BM). We aimed to investigate how type IV collagen (COL4) … Background Idiopathic pulmonary fibrosis (IPF) is characterised by damage to the epithelial layer, closely associated with the alveolar basement membrane (BM). We aimed to investigate how type IV collagen (COL4) in the BM changes with the progression of IPF. Methods COL4 synthesis (PRO-C4) was detected in blood by the nordicPRO-C4 biomarker in patients with IPF from the two prospective, multicentre, observational, longitudinal cohorts, pulmonary fibrosis biomarker (PFBIO) and prospective observation of fibrosis in the lung clinical endpoints (PROFILE). PRO-C4 trajectories over 12 months were compared between progressors and non-progressors by linear mixed effects regression models. Rate of change in PRO-C4 and lung function were compared by Bayesian bivariate longitudinal models. Cox proportional hazards models analysed baseline PRO-C4 and 3 years mortality. COL4 staining in IPF and non-IPF lungs was evaluated by immunohistochemistry. Results In PFBIO and PROFILE, 51/220 (23.2%) and 221/459 (48.1%) patients, respectively, had progressive disease at 12 months. Longitudinal PRO-C4 levels were higher in progressors versus non-progressors (average differences: PFBIO 21.5% (95% CI 3.4% to 42.9%, p=0.0184); PROFILE 10.9% (95% CI 0.8% to 22.1%; p=0.0340). Monthly rate of change in PRO-C4 was steeper in non-survivors versus survivors (mean difference up to 3.12% (95% CI 0.35% to 5.91%)) and was inversely correlated with the change in lung function. High baseline PRO-C4 was associated with increased mortality risk in PFBIO (HR 2.55 (95% CI 1.27 to 5.12), p=0.0083). COL4 staining was higher in IPF versus non-IPF lung but was less obvious in end-stage tissue. Conclusions High and increasing serological PRO-C4 levels were prognostic for progression in two independent IPF cohorts. This study suggests that COL4 synthesis assessed by PRO-C4 is a pathologically relevant biomarker of alveolar BM repair in IPF.

Efficacy and safety of imatinib in patients with COVID-19: a systematic review and meta-analysis

2025-06-19

Liang Li , Chengxiao Zhao , Siyuan Hou | Wiener klinische Wochenschrift

Social determinants of health, early diagnosis, and ageing in patients with interstitial lung disease

2025-06-19

Abebaw Mengistu Yohannes | Expert Review of Respiratory Medicine

Interstitial lung disease (ILD) is a heterogenous, chronic, progressive lung disease characterized by thickening and scar fibrosis of lung tissue, interstitial alveolar damage, severe airways limitations, and impaired gas exchange … Interstitial lung disease (ILD) is a heterogenous, chronic, progressive lung disease characterized by thickening and scar fibrosis of lung tissue, interstitial alveolar damage, severe airways limitations, and impaired gas exchange which leads to breathlessness and fatigue. Based on the available literature, only a few studies were identified that examined social determinants of health (SDOH) in the early diagnosis of ILD. The findings highlighted that those patients from low socioeconomic status and highly deprived communities had greater barriers in accessing healthcare, delayed diagnosis of ILD and receiving lung transplant surgery. We discuss the challenges encountered by both patients and physicians for early diagnosis and suggest potential strategies to identify and accelerate treatment of patients with ILD. SDOH exerts substantial burdens upon patients with ILD. Delay in the diagnosis of ILD associated with increased disease burden, elevated stress, anxiety, depression, frequent acute exacerbations, and premature death. SDOH heavily affects patients from low socioeconomic status and disadvantaged communities. Innovative strategies are required to address healthcare disparities on early diagnosis and treatment of ILD. Thus, patients with ILD and with identified SDOH may need dedicated additional support to improve care and focused areas for future research.

Up-to-date therapy of interstitial lung processes

2025-06-19

Martina Šterclová | Vnitřní lékařství

Predicting biomarkers of progressive pulmonary fibrosis: morphological, cytokine profile, and clinical portrait

2025-06-19

Nicol Bernardinello , Federica Pezzuto , Lauren D’Sa +7 more | Frontiers in Immunology

Objective The term progressive pulmonary fibrosis (PPF) refers to a specific disorder that becomes worse despite optimal treatment. The pathogenic explanation of this progressive worsening is still to be found. … Objective The term progressive pulmonary fibrosis (PPF) refers to a specific disorder that becomes worse despite optimal treatment. The pathogenic explanation of this progressive worsening is still to be found. In this study, we explored whether any histological, molecular, radiological, or clinical features could predict a progressive phenotype in patients with fibrotic interstitial lung diseases. Methods Two hundred and fifteen patients with PPF other than idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD) were followed in our ILD clinic between January 2016 and May 2023. Based on tissue block availability, 48 patients were definitively enrolled. Progression was defined according to the most recent guidelines. Clinical, radiological, and functional data were also collected retrospectively and correlated with tissue morphological and molecular cytokine profiles. Results Fifteen patients were classified as progressors (PPF) and 33 as non-progressors (nPPF) with similar age at diagnosis and gender. PPF showed a higher prevalence of traction bronchiectasis (80% vs. 27%; p=&lt;0.001) at CT scan and lower functional parameters [FVC: 2.42 L vs. 3.37 L; p=0.004; TLC: 3.83 L vs. 4.65 L; p=0.027] at diagnosis. Lung specimens revealed a significant overexpression of IL9 in the PPF compared to the nPPF group (p=0.049). Boruta algorithm analysis showed that lymphoid aggregates and traction bronchiectasis at diagnosis are the most important variables in determining the PPF status. Conclusions The present results increase the understanding of the pathological mechanisms of PPF, offering potential avenues for improved prognostication and therapeutic intervention.

Systemic lupus erythematosus and ANCA-associated vasculitis overlap with progressive interstitial lung disease: A narrative review with case illustration

2025-06-18

Anamitra Hait , N. Gaoudam , Sivaraman Kannan +1 more | Romanian Journal of Rheumatology

Background. Overlap syndromes involving systemic lupus erythematosus (SLE) and ANCA-associated vasculitis (AAV) are increasingly recognized but remain diagnostically and therapeutically challenging – especially when complicated by progressive interstitial lung disease … Background. Overlap syndromes involving systemic lupus erythematosus (SLE) and ANCA-associated vasculitis (AAV) are increasingly recognized but remain diagnostically and therapeutically challenging – especially when complicated by progressive interstitial lung disease (ILD) of the usual interstitial pneumonia (UIP) pattern. The presence of dual seropositivity, extrapulmonary manifestations such as scleritis, and atypical ILD patterns complicates clinical decision-making. Objective. To provide a comprehensive narrative review of SLE–ANCA overlap syndromes with a focus on interstitial lung involvement, supported by a clinically illustrative case of a patient with SLE, ANCA positivity, anterior scleritis, and UIP-pattern ILD. Methods. A selective, non-systematic review of the literature (2000–2025) was performed across PubMed, Scopus, and Google Scholar. Seven original studies were included and analyzed to identify clinical, serological, radiological, and histopathological patterns in SLE–ANCA overlap syndromes with ILD. Data were summarized narratively and presented in comparative tables. Case summary. A 46-year-old female with a prior SLE diagnosis presented with exertional dyspnea, anterior scleritis, and radiological features consistent with UIP. She exhibited ANA and dual ANCA positivity, along with elevated inflammatory markers. Due to cyclophosphamide intolerance, she was treated with corticosteroids and rituximab. This regimen led to improved pulmonary function, radiological stability, and resolution of ocular inflammation. Conclusion. SLE–ANCA overlap with UIP-ILD represents a rare but clinically aggressive autoimmune intersection. Early diagnosis through extended serological testing, high-resolution imaging, and multidisciplinary evaluation is essential. B-cell–targeted therapy, such as rituximab, offers a promising steroid-sparing option in complex presentations, particularly for patients intolerant to cyclophosphamide.

Role of inflammation-related genes as prognostic biomarkers and mechanistic implications in idiopathic pulmonary fibrosis

2025-06-18

Bing Bai , Wenfei Zhao , Fazhan Li +2 more | Frontiers in Genetics

Introduction Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disorder characterized by excessive fibrosis and structural remodeling of lung tissue. The role of inflammation in developing and progressing IPF … Introduction Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disorder characterized by excessive fibrosis and structural remodeling of lung tissue. The role of inflammation in developing and progressing IPF is increasingly recognized as critical. However, the precise mechanisms and pathways of inflammation in IPF remain unclear. This study aimed to identify inflammation-related genes in IPF and develop a prognostic risk model using machine learning approaches. Methods The IPF dataset GSE70866 from the Gene Expression Omnibus database was analyzed to identify inflammation-related genes. Unsupervised clustering algorithms were used to classify IPF samples, followed by weighted gene co-expression network analysis (WGCNA) to identify highly correlated genes. Least absolute shrinkage and selection operator (LASSO) regression was then applied, and the intersection of results pinpointed critical hub genes, primarily CCL2 and STAB1 . A rat model of pulmonary fibrosis was established, and lentivirus transfection was used to knock down CCL2 expression. The transfection effect and hub gene expression were validated using Quantitative polymerase chain reaction, Western blot, immunohistochemistry, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, and Masson’s trichrome staining. Levels of α-SMA and COL1A1 were also assessed. Results WGCNA and LASSO regression analyses identified CCL2 and STAB1 as significant contributors to IPF, closely associated with patient prognosis and immune cell infiltration. Protein-protein interaction network analysis established CCL2 as a novel biomarker for IPF. In a rat model of IPF, CCL2 expression was significantly elevated compared to that in the controls. Knockdown of CCL2 expression alleviated pulmonary fibrosis and reduced the expression of COL1A1 protein and α-SMA protein. CCL2 promotes the expression of COL1A1 protein and α-SMA proteins, suggesting that the mechanism of inflammation-induced pulmonary fibrosis may involve the regulation of COL1A1 and α-SMA by CCL2 . Discussion These findings establish CCL2 as a promising biomarker and potential therapeutic target for IPF.

Targeting Senescent Alveolar Type 2 Cells with a Gene-Editable FePt Dual-Atom Catalyst for Mitigating Idiopathic Pulmonary Fibrosis

2025-06-18

Qianglan Lu , Chengwei Ye , Wei Mao +7 more | ACS Nano

Idiopathic pulmonary fibrosis (IPF) remains an age-related, fatal, incurable, epithelial-driven fibrotic lung disease despite the availability of approved antifibrotic drugs. The medical need for effective antipulmonary fibrotic therapies is thus … Idiopathic pulmonary fibrosis (IPF) remains an age-related, fatal, incurable, epithelial-driven fibrotic lung disease despite the availability of approved antifibrotic drugs. The medical need for effective antipulmonary fibrotic therapies is thus very high. A promising therapeutic intervention for IPF is to target key cellular senescence processes in alveolar type 2 (AT2) cells. Herein, we introduce an inhalable gene-editable nanoplatform, comprising a CRISPR-Cas9 gene-editing system linked to a core FePt diatomic catalyst, encapsulated within a biocompatible hyaluronic acid (HA) surface layer (FePtR@HA). The FePt diatomic site facilitates H2O2 bridge adsorption, enabling efficient O-O bond cleavage and rapid catalytic conversion. The strong Fe-Pt interaction modulates the metal's d-band center, optimizing the adsorption of oxygen-containing intermediates. This precise regulation efficiently clears ROS, delivering robust antioxidant and antisenescence effects to AT2 cells. Simultaneously, the CRISPR-Cas9 gene editing system knocks down the pro-aging gene KAT7, reducing senescence-associated secretory phenotype (SASP) factors and further reversing AT2 cell senescence. Additionally, we demonstrated the antifibrotic efficacy of FePtR@HA in a lung-on-a-chip model, where it reprogrammed the fibrotic microenvironment, prevented myofibroblast recruitment to AT2 cells. Moreover, FePtR@HA showed satisfactory results in IPF mouse models, alleviating fibrosis and presenting a highly promising approach to combat the progression of IPF.

Revisiting pulmonary fibrosis: inflammatory dynamics of the lipofibroblast-to-inflammatory lipofibroblast-to-activated myofibroblast reversible switch

2025-06-18

Georgios‐Dimitrios Panagiotidis , Esmeralda Vásquez‐Pacheco , Xuran Chu +4 more | Frontiers in Immunology

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and irreversible lung damage. A key driver of disease progression is the … Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and irreversible lung damage. A key driver of disease progression is the phenotypic shift of lipofibroblasts (LIFs) into activated myofibroblasts (aMYFs), triggered by sustained epithelial injury, caused by inflammation, oxidative stress, viral infections (e.g., influenza, SARS-CoV-2), and metabolic dysfunction. Emerging evidence demonstrates that this transition is reversible, with pharmacological agents that promote aMYF-to-LIF reprogramming contributing to fibrosis resolution. The identification of inflammatory lipofibroblasts (iLIFs) highlights the importance of inflammation in fibrosis progression. Inflammation, mediated by IL-1β, IL-17A, and TGF- β, sustain aMYF activation, while immune cells shape fibrosis formation. This review combines current insights on the cellular and molecular pathways controlling fibroblast differentiation, highlighting key metabolic, immunologic, and oxidative stress-modulating targets for therapeutic intervention. Understanding and manipulating the LIF-iLIF-aMYF axis offers a promising strategy for reversing fibrosis and restoring pulmonary homeostasis in IPF.