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Background: Several genetic variants are associated with the risk of idiopathic pulmonary fibrosis (IPF). These have not been systematically reviewed., Methods: We searched the PubMed, Embase and GWAS Catalog databases for studies indexed between inception and 15 January 2024 describing genetic variants associated with IPF susceptibility. We included studies describing common associated single nucleotide polymorphisms (SNPs). We excluded studies describing rare variants, non-SNP variants and those without an allelic model analysis. We recorded study type, participant characteristics, genotyping methods, IPF diagnostic criteria, the SNPs and the respective genes, odds ratios, and other details. We also searched databases for functions of the identified genes., Results: The primary search retrieved 2697 publications; we included 42 studies. There were nine genome-wide association/linkage studies, while 27 were candidate gene studies. The studies included 22-11 160 IPF subjects. 88 SNPs in 58 genes or loci were found associated with IPF susceptibility. MUC5B rs35705950 was the most studied SNP. Most (n=51) SNPs were in the intronic or intergenic regions; only 11 were coding sequence variants. The SNPs had odds ratios ranging from 0.27 to 7.82 for an association with IPF. Only 22 SNPs had moderate-large effects (OR >1.5 or <0.67). Only 49.1% of the associated genes have a known functional role in IPF; the role of G protein-related signalling and transcriptional regulation (zinc-finger proteins) remain unexplored., Conclusion: Several common SNPs in over 50 genes have been found associated with IPF susceptibility. These variants may inform gene panels for future studies (PROSPERO CRD42023408912)., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2024.)

Rationale: Recent data suggest that the localisation of airway epithelial cells in the distal lung in idiopathic pulmonary fibrosis (IPF) may drive pathology. We set out to discover whether chemokines expressed in these ectopic airway epithelial cells may contribute to the pathogenesis of IPF., Methods: We analysed whole lung and single-cell transcriptomic data obtained from patients with IPF. In addition, we measured chemokine levels in blood, bronchoalveolar lavage (BAL) of IPF patients and air-liquid interface cultures. We employed ex vivo donor and IPF lung fibroblasts and an animal model of pulmonary fibrosis to test the effects of chemokine signalling on fibroblast function., Results: By analysis of whole-lung transcriptomics, protein and BAL, we discovered that CXCL6 (a member of the interleukin-8 family) was increased in patients with IPF. Elevated CXCL6 levels in the BAL of two cohorts of patients with IPF were associated with poor survival (hazard ratio of death or progression 1.89, 95% CI 1.16-3.08; n=179, p=0.01). By immunostaining and single-cell RNA sequencing, CXCL6 was detected in secretory cells. Administration of mCXCL5 (LIX, murine CXCL6 homologue) to mice increased collagen synthesis with and without bleomycin. CXCL6 increased collagen I levels in donor and IPF fibroblasts 4.4-fold and 1.7-fold, respectively. Both silencing of and chemical inhibition of CXCR1/2 blocked the effects of CXCL6 on collagen, while overexpression of CXCR2 increased collagen I levels 4.5-fold in IPF fibroblasts., Conclusions: CXCL6 is expressed in ectopic airway epithelial cells. Elevated levels of CXCL6 are associated with IPF mortality. CXCL6-driven collagen synthesis represents a functional consequence of ectopic localisation of airway epithelial cells in IPF., Competing Interests: Conflict of interest: N. Kaminski is a scientific founder at Thyron, and served as a consultant to Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, AstraZeneca, RohBar, Veracyte, Augmanity, CSL Behring, Galapagos and Thyron over the last 3 years, reports equity in Pliant and Thyron, and grants from Veracyte, Boehringer Ingelheim and BMS, and non-financial support from MiRagen and AstraZeneca. R. Lafyatis reports grants from Bristol Meyer Squib, Corbus, Formation, Moderna, Regeneron, Pfizer and Kiniksa, outside the submitted work, and served as a consultant with Bristol Meyers Squibb, Formation, Sanofi, Boehringer Ingelheim, Merck and Genentech/Roche. A. Prasse reports personal fees and non-financial support from Boehringer Ingelheim and Roche, personal fees from Novartis, AstraZeneca, Amgen, Pliant and Nitto Denko, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related., Methods: A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available., Results: GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997-1.000; p=0.245)., Conclusions: We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated., Competing Interests: Conflict of interest: R.G. Jenkins reports grants from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, RedX, Pliant and Genetech, consulting fees from Bristol-Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, Pliant and Chiesi, and advisory board participation with Boehringer Ingelheim, Galapagos, Vicore and Roche, outside the submitted work, and has a leadership role with NuMedii, and a leadership role and is a trustee for Action for Pulmonary Fibrosis. T.M. Maher reports consulting fees from Boehringer Ingelheim, Roche/Genentech, AstraZeneca, Bayer, Blade Therapeutics, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Respivant, Theravance and Veracyte, and lecture honoraria from Boehringer Ingelheim and Roche/Genentech, outside the submitted work. P.L. Molyneaux reports grants from AstraZeneca, consulting fees from Hoffman-La Roche, Boehringer Ingelheim, Trevi, Redex and AstraZeneca, and lecture honoraria from Boehringer Ingelheim and Hoffman-La Roche, outside the submitted work. L.V. Wain reports grants from Orion Pharma, GlaxoSmithKline, Genentech and AstraZeneca, consulting fees from Galapagos and Boehringer Ingelheim, travel support from Genentech, and advisory board participation with Galapagos, outside the submitted work; and is an Associate Editor for the European Respiratory Journal. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: A genomic classifier for usual interstitial pneumonia (gUIP) has been shown to predict histological UIP with high specificity, increasing diagnostic confidence for idiopathic pulmonary fibrosis (IPF). Whether those with positive gUIP classification exhibit a progressive, IPF-like phenotype remains unknown., Methods: A pooled, retrospective analysis of patients who underwent clinically indicated diagnostic bronchoscopy with gUIP testing at seven academic medical centres across the USA was performed. We assessed the association between gUIP classification and 18-month progression-free survival (PFS) using Cox proportional hazards regression. PFS was defined as the time from gUIP testing to death from any cause, lung transplant, ≥10% relative decline in forced vital capacity (FVC) or censoring at the time of last available FVC measure. Longitudinal change in FVC was then compared between gUIP classification groups using a joint regression model., Results: Of 238 consecutive patients who underwent gUIP testing, 192 had available follow-up data and were included in the analysis, including 104 with positive gUIP classification and 88 with negative classification. In multivariable analysis, positive gUIP classification was associated with reduced PFS (hazard ratio 1.58, 95% CI 0.86-2.92; p=0.14), but this did not reach statistical significance. Mean annual change in FVC was -101.8 mL (95% CI -142.7- -60.9 mL; p<0.001) for those with positive gUIP classification and -73.2 mL (95% CI -115.2- -31.1 mL; p<0.001) for those with negative classification (difference 28.7 mL, 95% CI -83.2-25.9 mL; p=0.30)., Conclusions: gUIP classification was not associated with differential rates of PFS or longitudinal FVC decline in a multicentre interstitial lung disease cohort undergoing bronchoscopy as part of the diagnostic evaluation., Competing Interests: Conflict of interest: S. Chaudhary reports consulting fees from Veracyte and Boehringer Ingelheim, outside the submitted work. S.S. Weigt reports consulting fees from Vercyte, and lecture honoraria from Genentech/Roche and Boehringer Ingelheim, outside the submitted work. J.V. Pugashetti is a member of the American Thoracic Society Clinical Problems Planning Committee, outside the submitted work. R. Keith reports lecture honoraria from Envisia, outside the submitted work. S. Oh reports lecture honoraria from Veracyte, outside the submitted work. F. Kheir reports lecture honoraria from Veracyte, Biodesix and UpToDate, and leadership roles with the American College of Chest Physicians and Society of Advanced Bronchoscopy, outside the submitted work. J. Solomon reports grants from Boehringer Ingelheim, Pfizer and NIH, and lecture honoraria from Boehringer Ingelheim, outside the submitted work. J.A. Lasky reports lecture honoraria from Veracyte and Boehringer Ingelheim, advisory board participation with Galecto, United Therapeutics and Genentech, and acts as CMO of the Pulmonary Fibrosis Foundation, outside the submitted work. J.M. Oldham reports grants from the National Institutes of Health (K23HL138190); reports consulting fees from Boehringer Ingelheim, Lupin Pharmaceuticals, AmMax Bio, Roche and Veracyte, a patent “TOLLIP TT genotype for NAC use in IPF” issued, advisory board participation for Endeavor Biomedicines, and acts as Associate Editor for CHEST and Program Committee for the American Thoracic Society, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Air pollutants are considered as non-negligible risk factors of idiopathic pulmonary fibrosis (IPF). However, the relationship between long-term air pollution and the incidence of IPF is unknown. Our objective was to explore the associations of air pollutants with IPF risk and further assess the modification effect of genetic susceptibility., Methods: We used land-use regression model estimated concentrations of nitrogen dioxide (NO 2 ), nitrogen oxides (NO x ) and particulate matter (fine particulate matter with diameter <2.5 μm (PM 2.5 ) and particulate matter with diameter <10 μm (PM 10 )). The polygenic risk score (PRS) was constructed using 13 independent single nucleotide polymorphisms. Cox proportional hazard models were used to evaluate the associations of air pollutants with IPF risk and further investigate the modification effect of genetic susceptibility. Additionally, absolute risk was calculated., Results: Among 433 738 participants from the UK Biobank, the incidence of IPF was 27.45 per 100 000 person-years during a median follow-up of 11.78 years. The adjusted hazard ratios of IPF for each interquartile range increase in NO 2 , NO x and PM 2.5 were 1.11 (95% CI 1.03-1.19), 1.07 (95% CI 1.01-1.13) and 1.09 (95% CI 1.02-1.17), respectively. PM 2.5 had the highest population attribution risk, followed by NO x and NO 2 . There were additive interactions between NO 2 , NO x and PM 2.5 and genetic susceptibility. Participants with a high PRS and high air pollution had the highest risk of incident IPF compared with those with a low PRS and low air pollution (adjusted hazard ratio: NO 2 3.94 (95% CI 2.77-5.60), NO x 3.08 (95% CI 2.21-4.27), PM 2.5 3.65 (95% CI 2.60-5.13) and PM 10 3.23 (95% CI 2.32-4.50))., Conclusion: Long-term exposures to air pollutants may elevate the risk of incident IPF. There are additive effects of air pollutants and genetic susceptibility on IPF risk., Competing Interests: Conflict of interest: The authors disclose that there are no potential competing financial interests or personal relationships that could affect the work reported in this article., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Whole genome sequencing (WGS) can detect variants and estimate telomere length. The clinical utility of WGS in estimating risk, progression and survival of pulmonary fibrosis patients is unknown., Methods: In this observational cohort study, we performed WGS on 949 patients with idiopathic pulmonary fibrosis or familial pulmonary fibrosis to determine rare and common variant genotypes, estimate telomere length and assess the association of genomic factors with clinical outcomes., Results: WGS estimates of telomere length correlated with quantitative PCR (R=0.65) and Southern blot (R=0.71) measurements. Rare deleterious qualifying variants were found in 14% of the total cohort, with a five-fold increase in those with a family history of disease versus those without (25% versus 5%). Most rare qualifying variants (85%) were found in telomere-related genes and were associated with shorter telomere lengths. Rare qualifying variants had a greater effect on telomere length than a polygenic risk score calculated using 20 common variants previously associated with telomere length. The common variant polygenic risk score predicted telomere length only in sporadic disease. Reduced transplant-free survival was associated with rare qualifying variants, shorter quantitative PCR-measured telomere lengths and absence of the MUC5B promoter (rs35705950) single nucleotide polymorphism, but not with WGS-estimated telomere length or the common variant polygenic risk score. Disease progression was associated with both measures of telomere length (quantitative PCR measured and WGS estimated), rare qualifying variants and the common variant polygenic risk score., Conclusion: As a single test, WGS can inform pulmonary fibrosis genetic-mediated risk, evaluate the functional effect of telomere-related variants by estimating telomere length, and prognosticate clinically relevant disease outcomes., Competing Interests: Conflict of interest: D. Zhang has received consulting fees from Boehringer Ingelheim and is supported by grants from the Stony Wold-Herbert Fund and the NHLBI (HL105323). C.A. Newton has received consulting fees from Boehringer Ingelheim and is supported by a career development award from the NHLBI. I. Noth has received consulting fees from Boehringer Ingelheim, Genentech and Sanofi-Aventis. F.J. Martinez reports grants from the NIH/NHLBI, Afferent/Merck, Bayer, Biogen, Nitto, Patara/Respivant, Promedior/Roche and Veracyte; consulting fees from Abvie, Boehringer Ingelheim, BMS, Bridge Biotherapeutics, CSL Behring, DevPro, Genentech, IQVIA, Lung Therapeutics, Sanofi, Shionogi, twoXAR and Veracyte; travel support from Boehringer Ingelheim, CSL Behring and Patara/Respivant; participation on advisory boards for Biogen and Boehringer Ingelheim; and honoraria from United Therapeutics. D. Goldstein is an employee of Actio Biosciences; La Jolla, CA, USA. C.K. Garcia reports support from NIH, the Department of Defense and Boehringer Ingelheim outside the scope of this work, lecture honoraria from Three Lakes Foundation and Stanford University, and other support from AstraZeneca. B. Wang, G. Povysil and G. Raghu have nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to their differentiation into myofibroblasts, thereby promoting the development of lung fibrosis. Bone morphogenetic protein 4 (BMP4), a multifunctional growth factor, is essential for the early stage of lung development; however, the role of BMP4 in modulating lung fibrosis remains unknown., Methods: The aim of this study was to evaluate the role of BMP4 in lung fibrosis using BMP4-haplodeleted mice, BMP4-overexpressed mice, primary lung fibroblasts and lung samples from patients with IPF., Results: BMP4 expression was downregulated in IPF lungs and fibroblasts compared to control individuals, negatively correlated with fibrotic genes, and BMP4 decreased with transforming growth factor (TGF)-β1 stimulation in lung fibroblasts in a time- and dose-dependent manner. In mice challenged with bleomycin, BMP4 haploinsufficiency perpetuated activation of lung myofibroblasts and caused accelerated lung function decline, severe fibrosis and mortality. BMP4 overexpression using adeno-associated virus 9 vectors showed preventative and therapeutic efficacy against lung fibrosis. In vitro , BMP4 attenuated TGF-β1-induced fibroblast-to-myofibroblast differentiation and extracellular matrix (ECM) production by reducing impaired mitophagy and cellular senescence in lung fibroblasts. Pink1 silencing by short-hairpin RNA transfection abolished the ability of BMP4 to reverse the TGF-β1-induced myofibroblast differentiation and ECM production, indicating dependence on Pink1-mediated mitophagy. Moreover, the inhibitory effect of BMP4 on fibroblast activation and differentiation was accompanied with an activation of Smad1/5/9 signalling and suppression of TGF-β1-mediated Smad2/3 signalling in vivo and in vitro ., Conclusion: Strategies for enhancing BMP4 signalling may represent an effective treatment for pulmonary fibrosis., Competing Interests: Conflict of interest: The authors have nothing to disclose., (Copyright ©The authors 2022.)

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers have the potential for guiding management in clinical practice. We assessed the prognostic role of serum biomarkers in three independent IPF cohorts: Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE)., Methods: In the AIPFR cohort, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. LASSO (least absolute shrinkage and selection operator) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at 1 year in the AIPFR cohort, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in the PROFILE cohort. Four significantly replicating biomarkers were aggregated into a progression index model based on tertiles of circulating concentrations., Results: 189 participants were included in the AIPFR cohort, 205 participants from the TLF cohort and 122 participants from the PROFILE cohort. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at 1 year. Proteomic data did not replicate. The progression index in the AIPFR, TLF and PROFILE cohorts predicted risk of progression, mortality and progression-free survival. A statistical model incorporating the progression index demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP (gender, age and physiology) score model alone in all cohorts, and significantly so within the incidence-based TLF and PROFILE cohorts., Conclusion: A panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients., Competing Interests: Conflict of interest: B. Clynick has nothing to disclose. Conflict of interest: T.J. Corte reports grants, personal fees and nonfinancial support from Boehringer Ingelheim, grants and personal fees from Roche, grants from Galapagos, Actelion and Bayer, outside the submitted work. Conflict of interest: H.E. Jo reports other (travel support and lecture fees) from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: I. Stewart has nothing to disclose. Conflict of interest: I.N. Glaspole reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: C. Grainge reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: T.M. Maher reports grants, personal fees and nonfinancial support from UCB, grants and personal fees from GlaxoSmithKline and AstraZeneca, personal fees from Boehringer Ingelheim, Roche, Bayer, Prometic, Samumed, Galapagos, Celgene, Indalo, Pliant, Blade Therapeutics, Respivant, Novartis and Bristol-Myers Squibb, other (stock options) from Apellis, outside the submitted work. Conflict of interest: V. Navaratnam has nothing to disclose. Conflict of interest: R. Hubbard has nothing to disclose. Conflict of interest: P.M.A. Hopkins has nothing to disclose. Conflict of interest: P.N. Reynolds has nothing to disclose. Conflict of interest: S. Chapman reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: C. Zappala has nothing to disclose. Conflict of interest: G.J. Keir has nothing to disclose. Conflict of interest: W.A. Cooper has nothing to disclose. Conflict of interest: A.M. Mahar has nothing to disclose. Conflict of interest: S. Ellis has nothing to disclose. Conflict of interest: N.S. Goh reports grants from the National Health Medical Research Council (NHMRC) (APP1066128, APP114776) and the Centre of Research Excellence in Pulmonary Fibrosis (CRE-PF), Australia (NHMRC GNT116371; 2017-2021), during the conduct of the study; the PROFILE study was funded by the Medical Research Council (G0901226) and GlaxoSmithKline R&D (CRT114316). Conflict of interest: E. De Jong has nothing to disclose. Conflict of interest: L. Cha has nothing to disclose. Conflict of interest: D.B.A. Tan has nothing to disclose. Conflict of interest: L. Leigh has nothing to disclose. Conflict of interest: C. Oldmeadow has nothing to disclose. Conflict of interest: E.H. Walters has nothing to disclose. Conflict of interest: R.G. Jenkins reports other (sponsored research agreements) from AstraZeneca, Biogen and Galecto, outside the submitted work; is on advisory boards for Boehringer Ingelheim, NuMedii, Promedior and Redex; reports lecture fees and consultancy for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Heptares, Pliant and Roche; and is a trustee for Action for Pulmonary Fibrosis. Conflict of interest: Y. Moodley reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF., Methods: To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments, we used genetic determinants of circulating proteins which reside cis to the encoded gene ( cis -single nucleotide polymorphisms (SNPs)), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalisation analyses to ensure that both the circulating proteins and IPF shared a common genetic signal., Results: MR analyses of 834 proteins found that a 1 sd increase in circulating galactoside 3(4)-l-fucosyltransferase (FUT3) and α-(1,3)-fucosyltransferase 5 (FUT5) was associated with a reduced risk of IPF (OR 0.81, 95% CI 0.74-0.88; p=6.3×10 -7 and OR 0.76, 95% CI 0.68-0.86; p=1.1×10 -5 , respectively). Sensitivity analyses including multiple cis -SNPs provided similar estimates both for FUT3 (inverse variance weighted (IVW) OR 0.84, 95% CI 0.78-0.91; p=9.8×10 -6 and MR-Egger OR 0.69, 95% CI 0.50-0.97; p=0.03) and FUT5 (IVW OR 0.84, 95% CI 0.77-0.92; p=1.4×10 -4 and MR-Egger OR 0.59, 95% CI 0.38-0.90; p=0.01). FUT3 and FUT5 signals colocalised with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%, respectively. Further transcriptomic investigations supported the protective effects of FUT3 for IPF., Conclusions: An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF., Competing Interests: Conflict of interest: T. Nakanishi has nothing to disclose. Conflict of interest: A. Cerani has nothing to disclose. Conflict of interest: V. Forgetta has nothing to disclose. Conflict of interest: S. Zhou has nothing to disclose. Conflict of interest: R.J. Allen has nothing to disclose. Conflict of interest: O.C. Leavy has nothing to disclose. Conflict of interest: M. Koido has nothing to disclose. Conflict of interest: D. Assayag reports grants and personal fees for consultancy from Boehringer Ingelheim Canada, personal fees for consultancy from Hoffman-LaRoche Canada, personal fees for lectures from AstraZeneca Canada, outside the submitted work. Conflict of interest: R.G. Jenkins reports grants from AstraZeneca, Biogen, Galecto and GlaxoSmithKline, personal fees from Boehringer Ingelheim, Daewoong, Galapagos, Heptares, Promedior and Roche, nonfinancial support from NuMedii and Redx, grants and personal fees from Pliant, other (trustee) from Action for Pulmonary Fibrosis, outside the submitted work. Conflict of interest: L.V. Wain reports grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: I.V. Yang reports grants from the NIH and personal fees from Eleven P15 related to research in pulmonary fibrosis, outside the submitted work; and has a patent “Circulating biomarkers of preclinical pulmonary fibrosis” pending. Conflict of interest: G.M. Lathrop has nothing to disclose. Conflict of interest: P.J. Wolters reports grants and personal fees from Boehringer Ingelheim and Roche/Genentech, personal fees from Gossamer Bio, Blade Therapeutics and Pliant, outside the submitted work. Conflict of interest: D.A. Schwartz reports grants from the NIH-NHLBI (R38-HL143511, T32-HL007085, UG3/UH3-HL151865, R01-HL149836, P01-HL0928701, UH2/3-HL123442, X01-HL134585 and R25-ES025476) and DOD Focused Program Grant W81XWH-17-1-0597, during the conduct of the study; personal fees from Eleven P15, outside the submitted work; and has a patent “Compositions and methods of treating or preventing fibrotic diseases” pending, a patent “Biomarkers for the diagnosis and treatment of fibrotic lung disease” pending and a patent “Methods and compositions for risk prediction, diagnosis, prognosis, and treatment of pulmonary disorders” issued. Conflict of interest: J.B. Richards has served as an advisor to GlaxoSmithKline and Deerfield Capital., (Copyright ©The authors 2022.)

Background: Alveolar epithelial cell dysfunction plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), but remains incompletely understood. Some monogenic forms of pulmonary fibrosis are associated with expression of mutant surfactant protein C (SFTPC). The commonest pathogenic mutant, I73T, mislocalises to the alveolar epithelial cell plasma membrane and displays a toxic gain of function. Because the mechanisms explaining the link between this mutant and IPF are incompletely understood, we sought to interrogate SFTPC trafficking in health and disease to understand the functional significance of SFTPC-I73T relocalisation., Methods: We performed mechanistic analysis of SFTPC trafficking in a cell model that reproduces the in vivo phenotype and validated findings in human primary alveolar organoids., Results: We show that wild-type SFTPC takes an unexpected indirect trafficking route via the plasma membrane and undergoes the first of multiple cleavage events before reaching the multivesicular body (MVB) for further processing. SFTPC-I73T takes this same route, but its progress is retarded both at the cell surface and due to failure of trafficking into the MVB. Unable to undergo onward trafficking, it is recycled to the plasma membrane as a partially cleaved intermediate., Conclusion: These data show for the first time that all SFTPC transits the cell surface during normal trafficking, and the I73T mutation accumulates at the cell surface through both retarded trafficking and active recycling. This understanding of normal SFTPC trafficking and how the I73T mutant disturbs it provides novel insight into SFTPC biology in health and disease, and in the contribution of the SFTPC mutant to IPF development., Competing Interests: Conflict of interest: J.A. Dickens has nothing to disclose. Conflict of interest: E.N. Rutherford has nothing to disclose. Conflict of interest: S. Abreu has nothing to disclose. Conflict of interest: J.E. Chambers has nothing to disclose. Conflict of interest: M.O. Ellis has nothing to disclose. Conflict of interest: A. van Schadewijk has nothing to disclose. Conflict of interest: P.S. Hiemstra has nothing to disclose. Conflict of interest: S.J. Marciniak has nothing to disclose., (Copyright ©The authors 2022.)

Interstitial lung diseases (ILDs) comprise a large and heterogeneous group of disorders of known and unknown aetiology characterised by diffuse damage of the lung parenchyma. In recent years it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis, known as progressive fibrosing ILD (PF-ILD). This is a phenotype that behaves similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILDs with similar clinical behaviour. This phenotype may occur in diseases displaying distinct aetiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering the progressive fibrosing phase. The crucial questions are: 1) why does a subset of patients develop a progressive and irreversible fibrotic phenotype even with appropriate treatment? and 2) what are the possible pathogenic mechanisms driving progression? Here, we provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, ageing, epigenetics, structural fibrotic distortion, aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct pro-fibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutic strategies., Competing Interests: Conflict of interest: M. Selman reports personal fees for consultancy from Boehringer Ingelheim, outside the submitted work. Conflict of interest: A. Pardo has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Idiopathic pulmonary fibrosis is a fatal age-related lung disease characterised by progressive and irreversible scarring of the lung. Although the details are not fully understood, there has been tremendous progress in understanding the pathogenesis of idiopathic pulmonary fibrosis, which has led to the identification of many new potential therapeutic targets. In this review we discuss several of these advances with a focus on genetic susceptibility and cellular senescence primarily affecting epithelial cells, activation of profibrotic pathways, disease-enhancing fibrogenic cell types and the role of the remodelled extracellular matrix., Competing Interests: Conflict of interest: T. Yanagihara reports personal fees from Prometic, outside the submitted work. Conflict of interest: S. Sato reports grants from Canadian Institute for Health Research, during the conduct of the study. Conflict of interest: C. Upagupta reports grants from Canadian Institute for Health Research, during the conduct of the study. Conflict of interest: M. Kolb reports grants from Canadian Institute for Health Research, during the conduct of the study; grants and personal fees from Roche, Boehringer Ingelheim and Prometic, grants from Actelion, Respivert and Alkermes, and personal fees from Genoa, Indalo and Third Pole, outside the submitted work., (Copyright ©ERS 2019.)

A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis.We investigated IPF pathogenesis using single-cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs.IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4 hi ), and one highly expressing SPP1 and MERTK (SPP1 hi ). SPP1 hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1 hi macrophages in normal lungs was strikingly increased in IPF lungs.Co-localisation and causal modelling supported the role for these highly proliferative SPP1 hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest that SPP1 hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease., Competing Interests: Conflict of interest: C. Morse has nothing to disclose. Conflict of interest: T. Tabib has nothing to disclose. Conflict of interest: J. Sembrat has nothing to disclose. Conflict of interest: K. Buschur has nothing to disclose. Conflict of interest: H. Trejo Bittar has nothing to disclose. Conflict of interest: E. Valenzi has nothing to disclose. Conflict of interest: Y. Jiang has nothing to disclose. Conflict of interest: D.J. Kass reports grants from NIH, during the conduct of the study; grants from Regeneron, outside the submitted work. Conflict of interest: K. Gibson has nothing to disclose. Conflict of interest: W. Chen has nothing to disclose. Conflict of interest: A. Mora has nothing to disclose. Conflict of interest: P.V. Benos has nothing to disclose. Conflict of interest: M. Rojas has nothing to disclose. Conflict of interest: R. Lafyatis has nothing to disclose., (Copyright ©ERS 2019.)

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown origin that is associated with high morbidity and mortality. In this perspective, we briefly review the current understanding of the pathophysiology of IPF and the importance of environmental triggers as a precipitant of disease. We discuss occult intrinsic and extrinsic environmental factors that affect the lung microenvironment and may contribute to the development and progression of disease. The clinical implications of this framework need to be further elucidated, because prompt identification and elimination of occult exposures may represent a novel treatment modality., Competing Interests: Conflict of interest: C. Sack has nothing to disclose. Conflict of interest: G. Raghu reports research grants for IPF studies from National Institutes of Health during the conduct of the study; has acted as a consultant on IPF studies for Biogen, BMS, Fibrogen, Gilead Sciences, Promedior, Roche-Genentech, Bellerophan and Nitto, has received personal fees, non-financial support and has acted as a consultant for Boehringer-Ingelheim and Sanofi, and has received personal fees and has acted as a consultant for Patara and Veracyte, outside the submitted work., (Copyright ©ERS 2019.)

Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF), it remains unclear if lung fibroblasts (FB) are the main therapeutic target.To resolve this question, we employed a comparative transcriptomic approach and analysed lung homogenates (LH) and FB derived from IPF patients treated with or without pirfenidone.In FB, pirfenidone therapy predominantly affected growth and cell division pathways, indicating a major cellular metabolic shift. In LH samples, pirfenidone treatment was mostly associated with inflammation-related processes. In FB and LH, regulated genes were over-represented in the Gene Ontology node "extracellular matrix". We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated IPF patients. Plasma levels of CEMIP were elevated in IPF patients compared to healthy controls and decreased after 7 months of pirfenidone treatment. CEMIP expression in FB was downregulated in a glioma-associated oncogene homologue-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration.Cumulatively, our approach indicates that pirfenidone exerts beneficial effects via its action on multiple pathways in both FB and other pulmonary cells, through its ability to control extracellular matrix architecture and inflammatory reactions., Competing Interests: Conflict of interest: A. Olschewski reports grants and honoraria for speaking from Pfizer, outside the submitted work. Conflict of interest: W. Seeger reports personal fees from Pfizer, Novartis, United Therapeutics, Actelion, Vectura, Savara, Medspray and Bayer AG, outside the submitted work. Conflict of interest: H. Olschewski reports grants from Intermune/Roche, and grants and personal fees from Boehringer, outside the submitted work. All other authors have nothing to disclose., (Copyright ©ERS 2018.)

Lung fibrosis can be observed in systemic sclerosis and in idiopathic pulmonary fibrosis, two disorders where lung involvement carries a poor prognosis. Although much has been learned about the pathogenesis of these conditions, interventions capable of reversing or, at the very least, halting disease progression are not available. Recent studies point to the potential role of micro messenger RNAs (microRNAs) in cancer and tissue fibrogenesis. MicroRNAs are short non-coding RNA sequences (20-23 nucleotides) that are endogenous, evolutionarily conserved and encoded in the genome. By acting on several genes, microRNAs control protein expression. Considering the above, we engaged in a systematic review of the literature in search of overlapping observations implicating microRNAs in the pathogenesis of both idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). Our objective was to uncover top microRNA candidates for further investigation based on their mechanisms of action and their potential for serving as targets for intervention against lung fibrosis. Our review points to microRNAs of the -29 family, -21-5p and -92a-3p, -26a-5p and let-7d-5p as having distinct and counter-balancing actions related to lung fibrosis. Based on this, we speculate that readjusting the disrupted balance between these microRNAs in lung fibrosis related to SSc and IPF may have therapeutic potential., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com, (Copyright ©ERS 2017.)

Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year -1 and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis.Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive., (Copyright ©ERS 2016.)

Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis.We retrospectively analysed all the genetic diagnoses made between 2007-2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival.237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40-60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046).TERT/TERC DAV were associated with specific clinical and biological features and reduced transplant-free survival., (Copyright ©ERS 2016.)

Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF., (Copyright ©ERS 2015.)

Throughout the past decade, there have been substantial advances in understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recently, several large genome-wide association and linkage studies have identified common genetic variants in more than a dozen loci that appear to contribute to IPF risk. In addition, family-based studies have led to the identification of rare genetic variants in genes related to surfactant function and telomere biology, and mechanistic studies suggest pathophysiological derangements associated with these rare genetic variants are also found in sporadic cases of IPF. Current evidence suggests that rather than existing as distinct syndromes, sporadic and familial cases of IPF (familial interstitial pneumonia) probably reflect a continuum of genetic risk. Rapidly evolving bioinformatic and molecular biology techniques, combined with next-generation sequencing technologies, hold great promise for developing a comprehensive, integrated approach to defining the fundamental molecular mechanisms that underlie IPF pathogenesis., (Copyright ©ERS 2015.)

The prevalence of obstructive sleep apnoea (OSA) is continuously increasing in patients with idiopathic pulmonary fibrosis (IPF) and, for the first time, the recent IPF guidelines recognise OSA as an important associated comorbidity that can affect patient's survival. Thus, it becomes conceivable that clinicians should refer patients with newly diagnosed IPF to sleep centres for the diagnosis and treatment of OSA as well as for addressing issues regarding the reduced compliance of patients with continuous positive airway pressure therapy. The discovery of biomarkers common to both disorders may help early diagnosis, institution of the most appropriate treatment and follow-up of patients. Better understanding of epigenetic changes may provide useful information about pathogenesis and, possibly, development of new drugs for a dismal disease like IPF., (Copyright ©ERS 2015.)

In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage. The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation. Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (p<0.05). The frequency of C282Y, S65C and H63D HFE allelic variants was markedly higher in IPF compared with controls (40.4% versus 22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4±56.0, HFE wild type (wt) 59.4±36.4 and controls 16.7±11.8 fluorescence units per 10(5) BAL cells; p=0.028 HFE variant versus HFE wt, p=0.006 HFE wt versus controls). The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF., (Copyright ©ERS 2015.)

Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the U.S.A., Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p<0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients., (© ERS 2014.)

Idiopathic pulmonary fibrosis (IPF) is marked by a very disappointing survival rate and still represents a clinical dilemma. According to the current pathogenic hypothesis, chronic damage of the alveolar epithelium is followed by abnormal tissue repair and impairment of the alveolar structure. This process is driven by pathogenic events very similar to cancer, including epigenetic and genetic changes, altered response to regulatory signals, abnormal expression of microRNAs and activation of specific signalling pathways. IPF also resembles cancer with regard to its poor response to medical treatment and prognosis, which is very often worse than many cancers. We have hypothesised that IPF might be assimilated to a neoproliferative disorder of the lung. Viewing IPF as a cancer-like disease may satisfy the need for a better understanding of the pathogenesis of IPF by exploiting the large amount of knowledge that cancer biology evokes. The recognition of common pathogenic pathways between the two diseases may stimulate new clinical trials with cancer drugs, different drug combinations and different lines of drugs, as already experimented in oncology. Moreover, the concept of IPF as a cancer-like disorder may improve the attention given to this dreadful disease on a public, political and healthcare level.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease that results in increasing morbidity. To date there is only one licensed therapy for this condition and other agents are needed for this attritional disease. Efforts to study other agents have been obstructed by an increasing division of opinion about the most clinically meaningful end-point of phase III clinical trials to demonstrate efficacy. Many clinicians believe that an agent that impedes progression of the disease is more than acceptable and will encourage the pharmaceutical industry to further develop their IPF programmes. We have been impressed by the behavioural and biological similarities of cancer and IPF, and wondered if lessons could be learned about clinical trial design from lung cancer studies. Here, we set out our arguments that the similarities with cancer justify comparing the magnitude of therapeutic effects in clinical trials in nonsmall cell lung cancer with those in successful trials in IPF. We demonstrate that efficacy is of a similar magnitude in the two chronic lung diseases. We recommend that the demonstration of similar magnitudes of progression-free disease effect in IPF, using appropriate indices, should be considered as clinically meaningful benefit in future phase III clinical trials of novel therapies.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with unknown pathogenesis. The WNT/β-catenin pathway has recently been reported to be operative in epithelial cells in IPF. Dickkopf (DKK) proteins are known to regulate WNT signalling via interaction with Kremen (KRM) receptors, yet their expression and role in the adult lung and in IPF has not been addressed. We analysed the expression, localisation and function of DKK and KRM proteins in IPF lungs using Western blotting, quantitative RT-PCR, immunohistochemistry, ELISA and functional in vitro studies. Enhanced expression of DKK1 and DKK4 and KRM1 was detected in lung homogenates of IPF patients compared with transplant donors. Immunohistochemistry revealed that DKK1 was predominantly localised in basal bronchial epithelial cells. Furthermore, prominent expression of all proteins was observed in hyperplastic alveolar epithelial cells in IPF. Quantitative measurement of DKK1 revealed enhanced protein expression in the bronchoalveolar lumen of IPF patients. Finally, functional studies using human bronchial and alveolar epithelial cell lines demonstrated that WNT-induced epithelial cell proliferation is regulated by DKK1 in a dose-dependent fashion. In summary, DKK proteins are expressed in the lung epithelium in IPF. DKK proteins influence epithelial cell proliferation and may, therefore, be suitable therapeutic targets for IPF.

Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case-control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37+/-0.7 mmHg (0.049+/-0.093 kPa) per month) compared to GA genotype (0.12+/-1 mmHg (0.016+/-0.133 kPa) per month) and GG genotype (0.2+/-0.6 mmHg (0.027+/-0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.