Am J Respir Crit Care Med. 2025 Jun 18. doi: 10.1164/rccm.202501-0317OC. Online ahead of print.

ABSTRACT

RATIONALE: Clinical measures of progressive pulmonary fibrosis (PPF) have been proposed, but their clinical utility remains unclear.

OBJECTIVES: To determine performance characteristics of lung function-based PPF measures, including new guideline criteria for discriminating clinically relevant outcomes.

METHODS: A multicenter retrospective cohort analysis was performed to assess the performance characteristics of eight categorical measures of forced vital capacity (FVC) and diffusion capacity (DLCO) decline, along with PPF guideline criteria (requiring two of the following: worsening respiratory symptoms, absolute decline in FVC ≥5% or DLCO ≥15%, or radiological progression) for discriminating two-year death or lung transplant among fibrotic ILD patients from the United States, United Kingdom and Canada (n=2727). The net benefit of the top performing measures to inform treatment initiation were compared using decision curves.

RESULTS: PPF classified according to relative decline in FVC of 10%, relative decline in DLCO of 15% and PPF guideline criteria displayed best overall test performance, with area under the receiver operator curves of 0.67-0.68. Specificity was higher than sensitivity for all evaluated measures, with relative measures of lung function decline outperforming absolute measures. The net benefit of stand-alone relative decline in FVC ≥10% and DLCO ≥15% was similar to PPF guideline criteria across the range of treatment probability thresholds.

CONCLUSION: Classifying PPF by stand-alone measures of FVC and DLCO decline provides similar clinical utility as PPF guideline criteria. Top performing physiology-based measures of PPF discriminate outcomes with high specificity, but low sensitivity.

PMID:40530983 | DOI:10.1164/rccm.202501-0317OC

Breathe (Sheff). 2025 Jun 17;21(2):240259. doi: 10.1183/20734735.0259-2024. eCollection 2025 Apr.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are characterised by an irreversible progression of pulmonary fibrosis and functional lung decline. Current antifibrotic therapies (nintedanib and pirfenidone for IPF and nintedanib for PPF) can reduce disease progression but not halt or reverse it. PPF and IPF share common pathophysiological pathways that need to be further elucidated for the development of novel therapeutic strategies. The educational aim of this review is to explain the pathogenic pathways that have led to the discovery of new therapeutic agents and their favourable implementation in phase 2 and 3 studies. This includes phosphodiesterase 4 inhibitors, αvβ6 and αvβ1 integrin inhibitors, lymphosphatidic acid antagonists, inhaled treprostinil, hedgehog inhibitors, tyrosine kinase inhibitors and angiotensin type 2 receptor agonists. The aim is also to better understand current therapeutic challenges and future perspectives, including cellular therapies, exosomes and their cargoes, as well as the integration of transcriptomics and proteomics, plus gene therapy.

PMID:40529319 | PMC:PMC12171857 | DOI:10.1183/20734735.0259-2024

Expert Rev Respir Med. 2025 Jun 17. doi: 10.1080/17476348.2025.2519861. Online ahead of print.

ABSTRACT

INTRODUCTION: Acute exacerbations in interstitial lung diseases, especially idiopathic pulmonary fibrosis, remain a significant clinical challenge associated with high mortality. Previously used empirical immunosuppressive therapies, notably cyclophosphamide, have proven ineffective.

AREAS COVERED: A literature search was conducted using the PubMed and ClinicalTrials.gov (NCT) databases for studies published up to March 2025. This review summarizes recent randomized clinical trial data on acute exacerbations, highlighting negative results for cyclophosphamide and recombinant thrombomodulin and positive preventive effects of antifibrotics such as nintedanib and pirfenidone. The evidence supporting vaccination strategies, methodological limitations in trial design, and diagnostic challenges are also discussed.

EXPERT OPINION: Shifting clinical practice away from harmful therapies toward precision medicine approaches, utilizing biomarkers, preventive antifibrotic strategies, and novel therapeutic targets, is essential. International collaboration in clinical research is crucial to improve patient outcomes.

PMID:40526976 | DOI:10.1080/17476348.2025.2519861

JCI Insight. 2025 Jun 17:e189636. doi: 10.1172/jci.insight.189636. Online ahead of print.

ABSTRACT

The gain-of-function MUC5B promoter variant is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF). However, its impact on protein expression in both non-fibrotic control and IPF lung specimens have not been well characterized. Utilizing laser capture microdissection coupled to mass spectrometry (LCM-MS), we investigated the proteomic profiles of airway and alveolar epithelium in non-fibrotic controls (n = 12) and IPF specimens (n = 12), stratified by the MUC5B promoter variant. Through qualitative and quantitative analyses, as well as pathway analysis and immunohistological validation, we have identified a distinct MUC5B-associated protein profile. Notably, the non-fibrotic control alveoli exhibited substantial MUC5B-associated protein changes, with an increase of IL-3 signaling. Additionally, we found that epithelial cells overlying IPF fibroblastic foci cluster closely to alveolar epithelia and express proteins associated with cellular stress pathways. In conclusion, our findings suggest that the MUC5B promoter variant leads to protein changes in alveolar and airway epithelium that appears to be associated with initiation and progression of lung fibrosis.

PMID:40526433 | DOI:10.1172/jci.insight.189636

J Clin Ultrasound. 2025 Jun 16. doi: 10.1002/jcu.70003. Online ahead of print.

ABSTRACT

PURPOSE: The diagnosis of interstitial lung disease (ILD) is primarily based on clinico-radiological findings, often requiring multidisciplinary discussion (MDD) for confirmation. Lung ultrasound (LUS) is a safe, non-invasive, bedside tool that has been explored for ILD assessment.

METHODS: We conducted a hospital-based, single-center, cross-sectional diagnostic accuracy study on patients with clinical suspicion of ILD. All patients underwent routine blood tests, lung function tests, LUS, and high-resolution computed tomography (HRCT) following a standardized protocol. LUS assessed pleural abnormalities, including thickening, shredding, and B-lines.

RESULTS: The study included 56 patients (mean age 54.79 ± 11.88 years) with a female predominance (57.14%). Diagnoses included connective tissue disease-related ILD (26.79%), idiopathic pulmonary fibrosis (21.43%), non-specific interstitial pneumonia (12.50%), hypersensitivity pneumonitis (10.71%), sarcoidosis (7.14%), and no ILD (17.86%). LUS demonstrated a sensitivity of 91.30%, specificity of 80.00%, diagnostic accuracy of 89.29%, and a diagnostic odds ratio of 41.55. The receiver-operating characteristic (ROC) curve for ultrasound B-lines had an AUC of 0.941 (p < 0.001).

CONCLUSION: The LUS B-lines score is a promising screening tool for ILD, with high diagnostic accuracy. Its bedside applicability makes it a valuable "point-of-care" test in ILD evaluation.

PMID:40524524 | DOI:10.1002/jcu.70003

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251323487. doi: 10.1177/17534666251323487. Epub 2025 Mar 13.

ABSTRACT

BACKGROUND: The 2018 guidelines on the diagnosis of idiopathic pulmonary fibrosis (IPF) conditionally recommend multidisciplinary discussion (MDD) for diagnostic decision-making. However, limited data concerning the diagnostic impact of MDD on interstitial lung diseases (ILDs) are available.

OBJECTIVES: The objective of this prospective study was to assess the impact of MDD at a tertiary referral ILD center on diagnostic trajectories, prognosis, and identification of potential treatable traits in ILD management.

DESIGN: This prospective study enrolled all consecutive adult ILD patients referred for MDD to a tertiary academic center in San Antonio, TX, USA from January 2017 to May 2020. The subjects were followed during a 3-year follow-up period after the MDD.

METHODS: Patients were stratified into three groups according to the pre-MDD diagnosis: unspecified ILD, IPF, and not IPF, and compared to the re-stratification post-MDD diagnosis into: unclassifiable ILD, IPF, and not IPF. The primary outcome was the percentage change in diagnostic trajectories after the MDD discussion.

RESULTS: A total of 201 ILD patients (61.7% male; mean (DS) age: 67.2 (10.4) years) were included in the study. The total diagnostic trajectory change occurred in 122 (60.7%) patients. The diagnostic trajectories changed in 40 (46.5%) patients in the IPF group and 8 (19.5%) in the non-IPF group (p-value = 0.0003). Patients with pre-MDD unspecified-ILD were classified as not-IPF in 32.4% (n = 24), IPF in 23% (n = 17), and unclassifiable-ILD in 44.6% (n = 33) post-MDD. Considering the post-MDD diagnosis, differences in mortality were detected among the three groups (p = 0.037).

CONCLUSION: Our results suggest that MDD has a significant impact not only on the diagnostic trajectories (DT) but also on the prognosis of patients with ILDs.

PMID:40524316 | DOI:10.1177/17534666251323487

Pulm Ther. 2025 Jun 16. doi: 10.1007/s41030-025-00302-5. Online ahead of print.

ABSTRACT

The spectrum of interstitial lung diseases (ILDs) includes a wide range of clinical entities with variable disease courses and prognoses. Several ILDs other than idiopathic pulmonary fibrosis (IPF) may exhibit a progressive fibrotic phenotype, with diverse clinical presentation, histopathological and radiological patterns, as well as varying rates of disease progression and uncertain epidemiology, but with a similar prognosis of untreated idiopathic pulmonary fibrosis with irreversible lung function deterioration, substantial worsening of quality of life and early mortality. The recently defined term "progressive pulmonary fibrosis" (PPF) stands as an opportunity to better classify patients with progressive fibrotic disease and other IPF, irrespective of the underlying ILD. The definition of disease progression, including factors such as pulmonary function test decline, radiological progression, and symptomatic worsening, was not adopted until recently, thus significantly impacting the certainty of current estimates of incidence and prevalence and prognostic outcomes. Understanding disease progression in the broad spectrum of potentially progressive ILDs is key for developing standardized management algorithms irrespective of the ILD diagnosis. Current evidence points towards the potential beneficial effect of antifibrotic drugs in lung function decline and overall outcomes in several non-IPF progressive ILDs showing progression despite optimal management.

PMID:40522429 | DOI:10.1007/s41030-025-00302-5

Mater Today Bio. 2025 May 29;32:101901. doi: 10.1016/j.mtbio.2025.101901. eCollection 2025 Jun.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive interstitial lung disease, for which no definitive cure exists so far. Although pirfenidone and nintedanib had been approved for IPF treatment, prolonged usage of these medications was often associated with adverse gastrointestinal and neurological side effects. There is still an urgent demand to develop highly effective anti-pulmonary fibrosis drugs with reduced toxicity profiles. Aster tataricus L . f. (Aster), a traditional Chinese medicine (TCM) used over a thousand years, contains a diverse array of bioactive compounds, including terpenoids, flavonoids, peptides, sterols, anthraquinones, phenylpropanoids, and coumarins. Our previous research demonstrated that intervaginal space injection (ISI) can enhance drug delivery to the lungs, improve bioavailability, and minimize systemic side effects. It is particularly suitable for particulate drug delivery. Furthermore, we have developed a novel freeze-thawing technique that facilitates the rapid formation of super self-assemblies from natural herbs. In the present study, we prepared super self-assemblies (ATSSA) and extracellular vesicles (EV) from the decoction of Aster. The results from the IPF mouse model revealed that the therapeutic efficacy of ATSSA and EV was comparable to or exceeded that of nintedanib, offering a promising avenue for the development of novel therapeutic agents for IPF.

PMID:40520551 | PMC:PMC12167058 | DOI:10.1016/j.mtbio.2025.101901

Front Pharmacol. 2025 May 30;16:1501085. doi: 10.3389/fphar.2025.1501085. eCollection 2025.

ABSTRACT

Characterized by sudden onset, accelerated disease progression, and high mortality rates, acute exacerbation (AE) represents the most critical clinical challenge faced by patients with idiopathic pulmonary fibrosis (IPF). The absence of standardized animal models that recapitulate human disease phenotypes remains a significant impediment to the study of AE-IPF. In this work, we conducted a systematic review of experimental protocols for acute exacerbation of pulmonary fibrosis (AE-PF) over the past 20 years relating to aspects such as animal species, drugs, drug doses, drug administration routes, and model characteristics, and summarized research progress on the mechanism underlying this condition. Statistical analysis revealed that bleomycin combined with lipopolysaccharide represents the predominant experimental paradigm for AE-PF, accounting for 26.3% (5/19) of all AE-PF models. Our analysis further showed that the major mechanisms involved in AE-IPF are inflammation, immune imbalance, oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis of alveolar epithelial cells.

PMID:40520197 | PMC:PMC12163009 | DOI:10.3389/fphar.2025.1501085

Thorax. 2025 Jun 15:thorax-2024-222306. doi: 10.1136/thorax-2024-222306. Online ahead of print.

ABSTRACT

RATIONALE: Inhalational exposures are associated with risk of developing interstitial lung disease (ILD), yet the relationship between specific exposures and ILD is poorly characterised.

OBJECTIVE: Identify inhalational exposures associated with ILD and estimate the effects of exposures on ILD risk.

METHODS: MEDLINE and EMBASE databases were searched from 1990 to 2022 to identify inhalational exposures associated with ILD diagnosis. ILDs where causality is well-established (hypersensitivity pneumonitis, pneumoconiosis) and sarcoidosis were excluded. Two independent reviewers screened abstracts with full-text review and data extraction of eligible studies. Where possible, data were pooled and multilevel meta-analysis was specified using a random effects model. Sources of heterogeneity and risk of bias were assessed.

MAIN RESULTS: 96 studies were included in the systematic review, representing 40 819 116 subjects (295 167 had ILD, 40 523 949 controls). For the meta-analysis, 54 studies were included (40 490 793 subjects: 273 899 ILD, 40 216 894 controls). Exposures associated with significantly increased ILD risk included smoking (OR 1.69, 95% CI 1.47 to 1.94), organic exposures (OR 1.56, 95% CI 1.12 to 2.16), metals (OR 1.52, 95% CI 1.07 to 2.16), dust (OR 1.45, 95% CI 1.20 to 1.76) and asbestos (OR 1.53, 95% CI 1.08 to 2.15). Silica and fumes had positive associations with ILD that trended towards significance.

CONCLUSIONS: This systematic review and multilevel meta-analysis is the first to comprehensively assess the effect of inhalational exposures on overall risk of ILD, with multiple putative exposures identified. Future work should investigate novel occupational exposures associated with ILD, characterise the gene-environment interaction and develop preventative strategies.

PROSPERO REGISTRATION NUMBER: CRD42022292908.

PMID:40518258 | DOI:10.1136/thorax-2024-222306

Int Immunopharmacol. 2025 Jun 14;161:115084. doi: 10.1016/j.intimp.2025.115084. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal, irreversible lung disorder with limited treatment options. Pathogenic drivers include fibroblast-to-myofibroblast transition, excessive collagen deposition, and inflammatory infiltration. Elevated circulating insulin-like growth factor-1 (IGF-1) levels and dysregulated activation of the IGF-1 receptor (IGF-1R) are implicated in multiple pathological conditions such as cancer, chronic inflammation, and fibrotic diseases. Linsitinib, a small-molecule tyrosine kinase inhibitor, selectively targets IGF-1R activation. However, its therapeutic potential and pharmacological mechanisms in IPF remain unexplored. In this study, we aimed to evaluate the efficacy and molecular basis of Linsitinib for IPF treatment. High-throughput sequencing revealed IGF-1 upregulation in the lung tissues of a murine IPF model. In vivo, oral Linsitinib attenuated fibrosis and inflammation in bleomycin-induced pulmonary fibrosis, inhibiting IGF-1R phosphorylation. In vitro, Linsitinib suppressed transforming growth factor β1-induced fibroblast-to-myofibroblast transition (marked by reduced alpha smooth muscle actin and fibronectin) and collagen biosynthesis (COL1A1, COL3A1) in primary lung fibroblasts. Transcriptomic profiling and lentiviral-based functional assays demonstrated that Linsitinib upregulated peroxisome proliferator-activated receptor gamma (PPARγ) expression by blocking IGF-1R phosphorylation, thereby promoting adipogenic transdifferentiation. Ex vivo, human IPF lung explants confirmed Linsitinib mitigated fibrosis and collagen accumulation via the IGF-1/IGF-1R/PPARγ axis. These findings suggest that Linsitinib exerts its effects against fibrosis by targeting IGF-1R-driven signaling pathways, making it a potential therapeutic agent for IPF.

PMID:40517732 | DOI:10.1016/j.intimp.2025.115084

Clin Transl Gastroenterol. 2025 Jun 13. doi: 10.14309/ctg.0000000000000874. Online ahead of print.

ABSTRACT

INTRODUCTION: Gastroesophageal reflux is common in respiratory disease, but the inter-play between gastrointestinal mechanisms that expose individuals to reflux and potentially aspiration, and lung mechanics and function remain incompletely understood. Our aim was to investigate this in patients with chronic obstructive pulmonary disease (COPD) and non-IPF interstitial lung disease (non-IPF ILD), and compare with our published findings in idiopathic pulmonary fibrosis (IPF).

METHODS: 57 patients with COPD (aged: 34-75yrs) and 64 with non-IPF ILD (22-75yrs) who underwent high-resolution impedance manometry and 24-hour pH-impedance, together with pulmonary function assessment were compared with 35 IPF patients (51-84yrs).

RESULTS: COPD patients were less likely to exhibit ineffective esophageal motility (IEM) and/or absent contractility (p=0.009; p=0.028), and tended to exhibit esophagogastric junction outflow obstruction (EGJOO) and/or hyper-contractility (p=0.09, p=0.14) than IPF and non-IPF ILD patients. Notably, integrated relaxation pressure correlated with esophageal length index (ELI) (p=0.048) and inspiratory LESP (p=0.003), with latter two correlating with each other (p<0.001). EGJOO patients tended to have fewer proximal reflux events and reduced pulmonary function; the latter inversely correlating with ELI (p<0.05).Non-IPF ILD patients were less likely to exhibit EGJOO than COPD patients (p=0.27), and less likely to exhibit IEM (p=0.07) than IPF patients. However, those with IEM or EGJOO, exhibited greater proportions of reflux events reaching the proximal esophagus than those with normal motility (p<0.03), which in contrast to IPF, appeared not to associate with worse pulmonary function.

CONCLUSIONS: Associations between esophageal motility, and lung mechanics and function, and consequently reflux, are very disease specific.

PMID:40512233 | DOI:10.14309/ctg.0000000000000874

Clin Respir J. 2025 Jun;19(6):e70087. doi: 10.1111/crj.70087.

ABSTRACT

BACKGROUND: The incidence of idiopathic pulmonary fibrosis (IPF) is increasing every year; however, the potential biological mechanisms have not been completely clarified. The objective of this study is to reveal the etiologic effects of circulating metabolites on IPF.

METHODS: This research evaluated the causal relationship between serum metabolites and IPF utilizing two-sample Mendelian randomization (MR) analysis. IVW served as the main method of analysis; concurrently, MR-Egger, weighted median, and MR-PRESSO acted as supplementary analyses. Sensitivity analyses were performed with Cochran's Q test, MR-Egger's intercept test, and leave-one-out method of analysis. All statistical analyses were accomplished in R software.

RESULTS: Our results showed that 23 metabolites have a causal connection with IPF. Following sensitivity analysis, 2 robust and 12 potential causal association pairs were identified among the known metabolites. These 14 causal pairs concerned six metabolites.

CONCLUSION: This study presents a novel perspective on potential mechanisms involved in IPF with important significance for screening, prevention, and treatment.

PMID:40512024 | DOI:10.1111/crj.70087

Ann Palliat Med. 2025 May;14(3):231-238. doi: 10.21037/apm-24-177.

ABSTRACT

BACKGROUND: The introduction of antifibrotic drugs elicited a significant paradigm shift in the treatment of fibrosing interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF). However, it remains unclear which clinical characteristics of IPF patients predicts therapeutic efficacy, and there has been limited investigation of the relationship between physical findings. The aim of this study was to investigate whether various clinical factors, including physical findings at the initiation of antifibrotic therapy, had an impact on the clinical response to treatment.

METHODS: We retrospectively examined baseline clinical characteristics of IPF patients to identify features associated with better responses to antifibrotic drugs. We identified 257 consecutive patients with progressive pulmonary fibrosis who received antifibrotic therapy between March 2009 and May 2021, including 153 patients treated with pirfenidone and 104 patients treated with nintedanib. Of these, 66 patients with IPF had comprehensive baseline data recorded at the time of therapy initiation, including gender, age, smoking history, symptoms, physical findings including digital clubbing, biomarkers, and pulmonary function. Based on pulmonary function at 6 months after initiation of treatment, these patients were classified into a non-deterioration group and a deterioration group. Baseline data at the initiation of antifibrotic therapy were compared between these two groups.

RESULTS: Twenty-two patients were classified into the deterioration group and 44 into the non-deterioration group. The annualized change in forced vital capacity (FVC) was -385.8±363.3 mL in the deterioration group and 94.1±207.0 mL in the non-deterioration group. The only significant difference in baseline characteristics between the groups was the presence of digital clubbing, observed in 5 of 22 patients (22.7%) in the deterioration group and in 22 of 44 patients (50.0%) in the non-deterioration group (P=0.04). Our findings indicate that IPF patients with digital clubbing experienced a smaller annual decline in FVC following antifibrotic therapy compared to those without digital clubbing.

CONCLUSIONS: These findings suggest that the presence or absence of digital clubbing in IPF patients may predict the annual rate of FVC decline following antifibrotic therapy. Antifibrotic drugs may be more effective in IPF patients who present with digital clubbing.

PMID:40511579 | DOI:10.21037/apm-24-177

Int J Mol Sci. 2025 Jun 4;26(11):5393. doi: 10.3390/ijms26115393.

ABSTRACT

In a susceptible individual, persistent, low-level injury to the airway epithelium initiates an exaggerated wound repair response, ultimately leading to idiopathic pulmonary fibrosis (IPF). The mechanisms driving this fibroproliferative response are not fully understood. Here, we review recent spatially resolved transcriptomics and proteomics studies that provide insight into two distinct matricellular microenvironments important in this pathological fibroproliferation. First, in response to alveolar epithelial injury, alveolar differentiation intermediate (ADI) basal cells arising from Secretoglobin (Scgb1a1) progenitors re-populate the injured alveolus remodeling the extracellular matrix (ECM). ADI cells exhibit an interconnected cellular stress response involving the unfolded protein response (UPR), epithelial-mesenchymal transition (EMT) and senescence pathways. These pathways reprogram cellular metabolism to support fibrillogenic ECM remodeling. In turn, the remodeled ECM tonically stimulates EMT in the ADI population, perpetuating the transitional cell state. Second, fibroblastic foci (FF) are a distinct microenvironment composed of activated aberrant "basaloid" cells supporting transition of adjacent mesenchyme into hyaluronan synthase (HAShi)-expressing fibroblasts and myofibroblasts. Once formed, FF are the major matrix-producing factories that invade and disrupt the alveolar airspace, forming a mature scar. In both microenvironments, the composition and characteristics of the ECM drive persistence of atypical epithelium sustaining matrix production. New approaches to monitor cellular trans-differentiation and matrix characteristics using positron emission tomography (PET)-magnetic resonance imaging (MRI) and optical imaging are described, which hold the potential to monitor the effects of therapeutic interventions to modify the ECM. Greater understanding of the bidirectional interrelationships between matrix and cellular phenotypes will identify new therapeutics and diagnostics to affect the outcomes of this lethal disease.

PMID:40508199 | DOI:10.3390/ijms26115393

Int J Mol Sci. 2025 May 31;26(11):5302. doi: 10.3390/ijms26115302.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with limited therapeutic options. This review focuses on the role of retinoids, particularly all-trans retinoic acid (atRA), and hypoxia in the pathogenesis of IPF. Despite an established understanding of genetic and environmental factors in IPF, the interplay between retinoid signaling and the response to hypoxia remains poorly explored due to its complexity. Preclinical evidence suggests that atRA could help reduce pulmonary fibrosis by modulating TGF-β signaling pathways and epithelial-to-mesenchymal transition (EMT). Additionally, we mention other diseases where a relationship between hypoxia and retinoids has been observed. We review how hypoxia, a key factor in the progression of IPF, may influence the efficacy of retinoid therapy. Combination strategies are explored to overcome hypoxia-induced treatment resistance. Finally, we address the complex role of retinoids in lung regeneration, balancing their potential benefits against the risk of exacerbating fibrotic processes. This review suggests that retinoids have potential as a treatment or adjuvant for IPF and highlights the need for further research to elucidate the precise mechanisms of retinoid action in IPF, particularly in hypoxia.

PMID:40508111 | DOI:10.3390/ijms26115302

J Clin Med. 2025 May 30;14(11):3862. doi: 10.3390/jcm14113862.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) and emphysema often coexist in patients with lung cancer (LC), forming a syndrome with combined pulmonary fibrosis and emphysema (CPFE). The three share the pathogenic mechanisms of smoking, chronic inflammation, and oxidative stress. The clinical management of CPFE patients is challenging, but its impact on tumor characteristics, acute exacerbation (AE), and prognosis is still controversial. The purpose of this study was to clarify the effect of CPFE on tumor biological behavior, AE risk, and survival outcome in patients with IPF-LC so as to optimize individualized treatment strategies. Methods: This was a retrospective and single-center study. Newly diagnosed LC patients with IPF, COPD, and normal lungs were recruited in the west China hospital. Patients with IPF were further categorized into CPFE-LC and isolated IPF-LC groups based on the presence of emphysema. Clinical and tumor features, lung function parameters, and prognosis were obtained and compared. Results: Patients with IPF and LC were more common in older men and heavy smokers. IPF-associated tumors had a higher proportion of carrying EGFR wild-type, occurring in the lower lobe of the lung and developing adenocarcinoma and squamous cell carcinoma. Among IPF-LC patients, 68.2% (103/151) met CPFE criteria. Pulmonary function tests demonstrated preserved VC% but significantly reduced FEV1/FVC in CPFE versus non-emphysema IPF (76.3% vs. 80.7%, p = 0.004), alongside elevated CPI and impaired DLCO. CPI ≥ 40 (HR = 2.087, 95%CI: 1.715-6.089, p = 0.012), combined with COPD (HR = 2.281, 95%CI: 1.139-4.569, p = 0.040), isolated IPF (HR = 5.703, 95%CI: 2.516-12.925, p < 0.001), and CPFE (HR = 6.275, 95%CI: 3.379-11.652, p < 0.001), were independent prognostic risk factors in LC patients. The incidence of treatment-induced AEs (49.5% vs. 29.2%, p = 0.038) and AE-related mortality (28.0% vs. 11.8%, p = 0.045) were significantly higher in the CPFE group than in the isolated IPF group. Logistic regression analysis showed that CPFE (OR: 3.494, 95%CI: 2.014-6.063, p = 0.001) was independently associated with the risk of AE-related mortality in patients with LC and IPF. Conclusions: Compared to LC patients with solely IPF, the presence of emphysema had no significant impact on overall survival, but CPFE increased the risk of treatment-triggered AE and was associated with AE-related mortality. In patients with LC, CPFE with AEs had a worse prognosis than IPF with AEs.

PMID:40507634 | DOI:10.3390/jcm14113862

Ann Am Thorac Soc. 2025 Jun 12. doi: 10.1513/AnnalsATS.202501-090RL. Online ahead of print.

NO ABSTRACT

PMID:40505144 | DOI:10.1513/AnnalsATS.202501-090RL

medRxiv [Preprint]. 2025 Jun 7:2025.06.06.25327886. doi: 10.1101/2025.06.06.25327886.

ABSTRACT

BACKGROUND: During the development of idiopathic pulmonary fibrosis (IPF), elastin is broken down and replaced with a stiffer substrate which interferes with normal breathing. This remodeling process releases the amino acids desmosine and isodesmosine and elastin degradation products (EDP), collectively known as elastokines, into the circulation and may act as a surrogate for the degree of matrix turnover. We examined the association between circulating and urinary elastokine concentrations, lung function, and transplant-free survival.

RESEARCH QUESTION: What are the associations between circulating and urinary elastokine concentrations (a marker of mature elastin turnover) with disease progression, as measured by transplant-free survival, in IPF?

STUDY DESIGN AND METHODS: Concentrations of desmosine and isodesmosine (elastokines) were measured via enzyme linked immunosorbent assay (ELISA) in the urine and serum of healthy volunteers and those with IPF. Samples were obtained from the University of Rochester Medical Center Interstitial Lung Disease (ILD) registry/biorepository (n = 81 with IPF and 24 healthy volunteers). We used linear and logistic regression modeling to determine associations between changes in urine EDP concentrations and lung function. Secondary analyses included the effect of anti-fibrotic medications on EDP concentration and assessment of associations between EDP concentrations at the time of diagnosis, lung function, and clinical outcomes.

RESULTS: Patients with IPF were older, more likely to be male, had ever smoked, and had worse lung function compared to healthy volunteers (p value <0.02 for all parameters). Patients with IPF had higher concentrations of elasotkines (p <0.001), and among those with IPF, higher elastokine concentrations were associated with reduced forced vital capacity (FVC, p = 0.026), and decreased three-year transplant-free survival (p=0.0005).

INTERPRETATION: Circulating and urinary elastokines are biomarkers of matrix turnover and are associated with relevant clinical outcomes in patients with IPF.

PMID:40502618 | PMC:PMC12155037 | DOI:10.1101/2025.06.06.25327886

medRxiv [Preprint]. 2025 Jun 4:2025.05.22.25328177. doi: 10.1101/2025.05.22.25328177.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and telomere length (TL) are both strongly linked to rare and common genetic variation. Shortened TL itself may be causal for IPF. Whether rare and common variants compete or cooperate to confer genetic risk of IPF uniformly is unknown.

METHODS: We used whole genome sequencing (WGS) data from a discovery case-control cohort sequenced at Columbia (777 IPF, 2905 controls) and validated findings using WGS data from Trans-Omics for Precision Medicine (TOPMed, 1148 IPF, 5202 controls) and the UK Biobank (UKBB, 2739 IPF, 395331 controls). In all cohorts, we identified rare damaging variants in disease-associated genes and computed control-normalized polygenic risk scores for IPF (IPF-PRS) and telomere length (TL-PRS). Telomere length of blood leukocytes was measured using a qPCR assay for two cohorts. We determined the association of the MUC5B rs35705950 polymorphism, an IPF-PRS excluding MUC5B (IPF-PRS-no MUC5B ), and a TL-PRS with IPF risk in the overall cohort and in subgroups stratified by genetic endotypes (rare variant carriers, non-carriers stratified by TL cutoffs). We calculated cross-validated area under the receiver operator curve (AUC) and compared the liability of IPF explained by genetic variables.

FINDINGS: We identified independent associations between IPF risk and rare variants, the MUC5B SNP, and both polygenic scores in the discovery cohort and replicated these findings in the TOPMed and UKBB cohorts. The adjusted effect size of the TL-PRS, which includes >180 SNPs not previously associated with IPF, was comparable to the IPF-PRS-no MUC5B in the discovery (ORTL-PRS 1.63 [95% CI 1.47, 1.81] vs. ORIPF-PRS 1.60 [1.44, 1.77]) and replication cohorts (TOPMed ORTL-PRS 1.47 [1.36, 1.59] vs. ORIPF-PRS 1.37 [1.25, 1.50]; UKBB ORTL-PRS 1.24 [1.19, 1.29] vs. ORIPF-PRS 1.25 [1.21, 1.30]). The TL-PRS incrementally improved disease prediction beyond known IPF common and rare genetic predictors and clinical variables in discovery (combined AUC: 0.89, pDelong = 0.006), TOPMed (combined AUC: 0.89, pDelong = 0.01), and UKBB cohorts (combined AUC: 0.77, pDelong = 0.03). Rare and common variants jointly contributed to genetic liability of IPF. The TL-PRS increased liability of IPF explained by 13% in the discovery cohort and 8% and 13% in the TOPMed and UKBB cohorts, respectively. In IPF subjects with damaging rare variants, the TL-PRS was consistently associated with disease risk whereas the IPF-PRS-no MUC5B was not. The TL-PRS also conferred nominally greater odds of disease risk than the IPF-PRS-no MUC5B in patients with shorter TL, in the discovery and UKBB cohorts. Together, 23-43% of IPF cases have damaging rare variants or telomeres <10 th percentile, where the TL-PRS represents a major unrecognized genetic risk factor.

INTERPRETATION: Common and rare genetic variation confer context-specific genetic risk in IPF competitively and cooperatively. In contrast to known IPF common risk variants, the TL-PRS, which includes >180 genetic loci not previously associated with IPF, increases the risk of disease specifically in certain IPF endotypes. Polygenic risk from telomere-associated common variants is a key feature of IPF genetic heterogeneity.

FUNDING: National Institutes of Health (NIH), Medical Research Council (MRC), National Institute for Health and Care Research (NIHR).

RESEARCH IN CONTEXT: Evidence before this study: We performed a search on PubMed for "common variants", "rare variants", "polygenic score", "endotype", and "IPF" on April 20 th , 2025, to identify integrated genetic studies of rare and common variants in IPF. We found no original articles that comprehensively examined common and rare IPF variants together. Nearly all articles analyzed common or rare variants in isolation; one article included both common and rare variant analyses but reported results separately without studying their combined effects. We identified numerous reviews that discuss or conceptualize the relative contributions of rare and common genetic risk to IPF risk; no studies provided or cited empiric data. Although "IPF endotypes" have been defined using transcriptomics and proteomics, we did not find any articles that utilized this terminology based on genetic factors, although several studies distinguish IPF with rare variants or telomere length below 10 th percentile. Added value of this study: We describe the first comprehensive survey of common and rare risk variants together in IPF and identify subtype-specific genetic risk factors that substantially improve genetic explanation and disease prediction. We uncover complex relationships between polygenic factors and rare variants, including preliminary evidence of polygenic modifiers in IPF carriers of rare damaging variants that might serve as an explanation for incomplete penetrance. Genetic studies in IPF have been limited by sample size leading to "missing heritability". We demonstrate value in leveraging large-scale genetic studies of causal molecular traits like telomere length to overcome these limitations and improve genetic understanding of IPF. These telomere-associated common variants are context-specific risk factors in certain endotypes, highlighting previously unrecognized genetic heterogeneity that will be important for future discovery of novel, reproducible genetic risk factors in IPF.Implications of all the available evidence: A genetic basis for disease heterogeneity allows for research that focuses on relevant endotypes instead of "all-comer" disease and advances precision medicine approaches to IPF. Polygenic factors that can modify the effects of a high-risk rare variant represent a target for understanding disease-modifying pathways in IPF.

PMID:40502585 | PMC:PMC12155034 | DOI:10.1101/2025.05.22.25328177