Pulmonology. 2025 Dec 31;31(1):2425503. doi: 10.1080/25310429.2024.2425503. Epub 2024 Nov 12.

ABSTRACT

Fibrotic hypersensitivity pneumonitis (f-HP) is an interstitial lung disease in which various antigens in susceptible individuals may play a pathogenetic role. This study evaluates the role of transbronchial lung cryobiopsy (TBLC) and bronchoalveolar lavage (BAL) in identifying a UIP-like pattern and its association with fibrosis progression. We conducted a multicentre retrospective cohort study of patients diagnosed with f-HP who underwent BAL and TBLC between 2011 and 2023. A UIP-like pattern was defined by the presence of (A) patchy fibrosis and fibroblastic foci or (B) honeycombing ± (A). We investigated BAL's role in predicting UIP-like patterns within a clinical-radiological-serological framework, examining disease progression in these patients using spirometry and mortality data. A total of 195 patients were enrolled, 59 (30%) of whom exhibited a UIP-like pattern. These patients showed greater lung function decline, lower BAL lymphocytosis (14.4% vs. 37.4%, p < 0.001), higher nintedanib prescription (35% vs. 14%, p < 0.001), and higher 10-year mortality (HR 2.8, 95% CI 1.3-5.8, p = 0.004). f-HP patients with a UIP-like pattern exhibit worse clinical outcomes and higher mortality. In cases of low BAL lymphocytosis with a high pre-test clinical suspicion of f-HP, lung biopsy may not be necessary as it increases the likelihood of identifying a UIP-like pattern.

PMID:39883494 | DOI:10.1080/25310429.2024.2425503

Pulmonology. 2025 Dec 31;31(1):2424637. doi: 10.1080/25310429.2024.2424637. Epub 2024 Nov 6.

NO ABSTRACT

PMID:39883507 | DOI:10.1080/25310429.2024.2424637

Front Med (Lausanne). 2025 Jan 15;11:1526531. doi: 10.3389/fmed.2024.1526531. eCollection 2024.

ABSTRACT

BACKGROUND: There is a paucity of real-world data on patients with interstitial lung diseases (ILDs) that are progressive, other than idiopathic pulmonary fibrosis (IPF), including treatment patterns and attitudes toward treatment. This study aimed to investigate the diagnosis, clinical characteristics, treatment paradigm and current decision-making practices of IPF and progressive pulmonary fibrosis (PPF) in a Japanese real-world setting.

METHODS: Data were drawn from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey with retrospective data collection of pulmonologists and rheumatologists in Japan from April to October 2022. Physicians provided data for up to 12 consecutive patients with a physician-confirmed diagnosis of progressive ILD; patients were also invited to complete patient self-completion forms. Analyses were descriptive.

RESULTS: A total of 63 physicians (43 pulmonologists and 20 rheumatologists) provided data on 312 patients with PPF and 70 patients with IPF. Patients had a mean (standard deviation [SD]) age at survey date of 68.0 (11.6) years, 43.5% were female, 50.3% were former smokers and 18.1% were employed full time. For breathlessness, 26.5% of patients had Grade 2 physician-reported breathlessness; this was 16.7% when reported by patients themselves. A total of 81.4% of patients were currently receiving treatment for ILD. Mean (SD) duration of current treatment was 1.5 (1.4) years. Slowing disease progression was the primary reason influencing physicians' choice of current ILD treatment (48.5%). A total of 16.0% had never been treated (most frequent physician-reported reason: disease was manageable without treatment, 55.7%) and 2.6% had treatment discontinued (most frequent reason: patient request, 70.0%). Physicians reported 82.3% of patients as fully compliant with their treatment regimen. As reported by patients themselves (n = 53), 49.1% never and 37.7% rarely missed a dose.

CONCLUSION: This analysis of real-world data from Japan provides insights into the clinical profile of patients with IPF and PPF in Japan, and highlights differences between physicians and patients in perception of symptom severity and attitudes to treatment.

PMID:39882519 | PMC:PMC11775758 | DOI:10.3389/fmed.2024.1526531

BMC Pulm Med. 2025 Jan 29;25(1):47. doi: 10.1186/s12890-025-03520-4.

ABSTRACT

BACKGROUND: Fibrotic types of interstitial lung abnormalities seen on high-resolution computed tomography scans, characterised by traction bronchiolectasis/bronchiectasis with or without honeycombing, are predictors of progression and poor prognostic factors of interstitial lung abnormalities. There are no reports on the clinical characteristics of fibrotic interstitial lung abnormalities on high-resolution computed tomography scans. Therefore, we aimed to examine these clinical characteristics and clarify the predictive factors of fibrotic interstitial lung abnormalities on high-resolution computed tomography scans.

METHODS: Clinical and paraclinical data of 164 patients enrolled in the initial year of a multicentre prospective observational study (Kumamoto interstitial lung abnormalities study in Japan) involving over 62,000 examinees during routine health examinations were analysed. Clinical laboratory evaluations are expressed as medians and interquartile ranges for each evaluation time point, and boxplots were created for graphical representation. The percentages of abnormal clinical laboratory results were compared between the groups using chi-square or Fisher's exact tests. Univariate or multivariate logistic regression analyses were performed to analyse the relationship between fibrotic interstitial lung abnormalities and other clinical factors.

RESULTS: Fibrotic interstitial lung abnormalities were observed on high-resolution computed tomography scans in 135 (82%) patients at the time of diagnosis. Multivariate analysis showed that older age (Odds ratio, 1.06; 95% confidence interval, 1.01-1.12; p = 0.021), auscultatory fine crackles (Odds ratio, 3.39; 95% confidence interval, 1.33-8.65; p < 0.01), and elevated serum surfactant protein-D (Odds ratio, 2.68; 95% confidence interval, 1.02-8.64; p = 0.045) were independent predictive factors of fibrotic interstitial lung abnormalities. The predicted area under the curve of the fibrotic interstitial lung abnormalities based on these three factors was 0.77 (95% confidence interval, 0.68-0.86). The proportion of undecided diagnoses in the fibrotic interstitial lung abnormalities group (14%) was significantly lower than that in the non-fibrotic interstitial lung abnormalities group (41%) (p = 0.0027).

CONCLUSIONS: Fine crackles on auscultation and elevated serum surfactant protein-D levels are predictors of fibrotic interstitial lung abnormalities in older patients with interstitial lung abnormalities. These findings may assist non-radiological physicians in referring patients to specialists for early intervention in progressive fibrotic interstitial lung diseases.

TRIAL REGISTRATION NUMBER/DATE: UMIN000045149/2021.12.1.

PMID:39881354 | DOI:10.1186/s12890-025-03520-4

Biochem Genet. 2025 Jan 29. doi: 10.1007/s10528-024-11012-z. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown pathogenesis with no effective treatment currently available. Given the regulatory roles of lncRNAs (TP53TG1, LINC00342, H19, MALAT1, DNM3OS, MEG3), miRNAs (miR-218-5p, miR-126-3p, miR-200a-3p, miR-18a-5p, miR-29a-3p), and their target protein-coding genes (PTEN, TGFB2, FOXO3, KEAP1) in the TGF-β/SMAD3, Wnt/β-catenin, focal adhesion, and PI3K/AKT signaling pathways, we investigated the expression levels of selected genes in peripheral blood mononuclear cells (PBMCs) and lung tissue from patients with IPF. Lung tissue and blood samples were collected from 33 newly diagnosed, treatment-naive patients and 70 healthy controls. Gene expression levels were analyzed by RT-qPCR. TaqMan assays and TaqMan MicroRNA assay were employed to quantify the expression of target lncRNAs, mRNAs, and miRNAs. Our study identified significant differential expression in PBMCs from IPF patients compared to healthy controls, including lncRNAs MALAT1 (Fold Change = 3.809, P = 0.0001), TP53TG1 (Fold Change = 0.4261, P = 0.0021), and LINC00342 (Fold Change = 1.837, P = 0.0448); miRNAs miR-126-3p (Fold Change = 0.102, P = 0.0028), miR-200a-3p (Fold Change = 0.442, P = 0.0055), and miR-18a-5p (Fold Change = 0.154, P = 0.0034); and mRNAs FOXO3 (Fold Change = 4.604, P = 0.0032) and PTEN (Fold Change = 2.22, P = 0.0011). In lung tissue from IPF patients, significant expression changes were observed in TP53TG1 (Fold Change = 0.2091, P = 0.0305) and DNM3OS (Fold Change = 4.759, P = 0.05). Combined analysis of PBMCs expression levels for TP53TG1, MALAT1, miRNA miR-126-3p, and PTEN distinguished IPF patients from healthy controls with an AUC = 0.971, sensitivity = 0.80, and specificity = 0.955 (P = 6 × 10-8). These findings suggest a potential involvement of the identified ncRNAs and mRNAs in IPF pathogenesis. However, additional functional validation studies are needed to elucidate the precise molecular mechanisms by which these lncRNAs, miRNAs, and their targets contribute to PF.

PMID:39881079 | DOI:10.1007/s10528-024-11012-z

Ann Am Thorac Soc. 2025 Jan 29. doi: 10.1513/AnnalsATS.202409-906OC. Online ahead of print.

ABSTRACT

RATIONALE: Tobacco smoking is a well-established risk factor for idiopathic pulmonary fibrosis (IPF), yet the influence of early-life tobacco exposure on future IPF risk remains poorly understood.

OBJECTIVES: To test the hypothesis that early-life tobacco exposure may elevate the risk of developing IPF, with this effect potentially modified by genetic susceptibility to IPF and mediated through accelerated biological aging.

METHODS: Using data from over 430,000 participants in the UK Biobank, we performed a prospective cohort study to examine the associations of maternal smoking around birth and age of smoking initiation with IPF risk. We evaluated the combined effects and interactions between early-life tobacco exposure and genetic susceptibility to IPF, quantified using polygenic risk scores. We assessed biological aging, as measured by telomere length and phenotypic age, as potential mediators in the associations between early-life tobacco exposure and IPF risk. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: Maternal smoking around birth was associated with a higher risk of IPF (HR: 1.26; 95% CI: 1.11-1.43). Compared to never-smokers, individuals who initiated smoking in childhood (HR: 3.65; 95% CI: 3.02-4.41), adolescence (HR: 2.64; 95% CI: 2.28-3.05), and adulthood (HR: 2.09; 95% CI: 1.79-2.44) exhibited increased IPF risk (P for trend < 0.001). An additive interaction was observed between age of smoking initiation and genetic risk for IPF. Individuals with high genetic risk, maternal smoking exposure, and childhood smoking initiation had a 16-fold greater risk of IPF (HR: 16.47; 95% CI: 9.57-28.32), compared to those with low genetic risk and no tobacco exposure. Telomere length and phenotypic age each mediated approximately 10% of the effect of maternal smoking on IPF, with weaker mediation effects observed for later ages of smoking initiation.

CONCLUSION: Early-life tobacco exposure may elevate the risk of IPF, with effect modified by genetic susceptibility and partially mediated through accelerated biological aging.

PMID:39879538 | DOI:10.1513/AnnalsATS.202409-906OC

PLoS One. 2025 Jan 29;20(1):e0316484. doi: 10.1371/journal.pone.0316484. eCollection 2025.

ABSTRACT

BACKGROUND AND AIMS: Predicting progression and prognosis in Interstitial Lung Diseases (ILD), especially Idiopathic Pulmonary Fibrosis (IPF) and Progressive Pulmonary Fibrosis (PPF), remains a challenge. Integrating patient-centered measurements is essential for earlier and safer detection of disease progression. Home monitoring through e-health technologies, such as spirometry and oximetry connected to smartphone applications, holds promise for early detection of ILD progression or acute exacerbations, enabling timely therapeutic interventions.

METHODS: The European ILD Registry Algorithm for Self-Assessment in ILD (eurILDreg ASA-ILD), developed by all eurILDreg principal investigators, includes questionnaires on symptom burden, respiratory infections, and quality of life (EQ5D VAS, K-BILD, LCQ). The algorithm also incorporates spirometry and oxygen saturation measurements, both at rest and during exercise (one-minute sit-to-stand test, 1STST). This ASA-ILD algorithm is integrated into the patientMpower Ltd. smartphone application, used for patient-led monitoring, research, and clinical care since 2016, and available on both Apple and Android platforms.

DISCUSSION: For patient-centered measurements, participants in the multicenter eurILDreg study will receive a patientMpower account, a handheld clinical-grade spirometer (Spirobank Smart, MIR, Italy), and a pulse oximeter (Nonin Medical, Inc. Plymouth, MN, USA), along with usage instructions. Artificial intelligence software (ArtiQ) will analyze spirometry maneuvers in real-time, ensuring compliance with recent ERS/ATS criteria and providing automated feedback. Pulse oximetry is integrated into the exercise testing within the application, following an automated in-app protocol developed with clinician involvement for safety and accuracy. The application will send reminders to participants to complete patient-reported outcome measures (PROMs) according to the study protocol.

CONCLUSION: This study is designed to explore the potential of e-Health technologies, such as home monitoring via spirometry and oximetry, integrated with the eurILDreg ASA-ILD algorithm and patientMpower app, to improve early detection and management of ILD. A pilot trial showed promising adherence to spirometry, indicating that digital health interventions could enhance patient care and outcomes in ILD.

TRIAL REGISTRATION: The ethics committee of the Justus-Liebig-University of Giessen has approved the eurILDreg and this substudy with the protocol reference number 111/08. The research was conducted strictly according to the principles of the Declaration of Helsinki. Patients were included into the registry upon having signed the informed consent. The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov (NCT02951416). EurILDreg is registered in German Clinical Trials Register, DRKS 00028968.

PMID:39879227 | DOI:10.1371/journal.pone.0316484

Respir Care. 2023 Dec 28;69(1):114-127. doi: 10.4187/respcare.11298.

ABSTRACT

BACKGROUND: People with interstitial lung disease (ILD) want to actively manage their condition; however, the effects of self-management interventions (SMIs) in this population have not been synthesized. This review summarizes the effects of SMIs on health-related quality of life (HRQOL), functional status, psychological and social factors, symptoms, exacerbations, health care utilization, and survival in people with ILD.

METHODS: The protocol of this systematic review was registered (PROSPERO ID: CRD42022329199). Six digital databases were searched in May 2022 with monthly updates until August 2023. Studies implementing SMIs in people with any type of ILD were included. Risk of bias (RoB) and quality of evidence were assessed with the Cochrane tool for RoB assessment and the grading of recommendations, assessment, development, and evaluations. Meta-analysis was used to summarize the results.

RESULTS: Four studies that examined 217 participants (81% male, 71 y old, 91% idiopathic pulmonary fibrosis) were included. SMIs were highly heterogeneous. Meta-analysis showed no difference in HRQOL (standardized mean difference: 0.08 [95% CI -0.21 to 0.37], P .58) nor in the secondary outcomes. No evidence for the effects of SMIs on functional capacity, exacerbations, and survival was found. The quality of evidence ranged from low to very low.

CONCLUSIONS: There is low to very low-quality evidence that SMIs have no effect in people with ILD. However, this conclusion is limited by high methodological heterogeneity. A consensus definition of SMIs is needed to implement more comparable interventions and strengthen results.

PMID:39878768 | DOI:10.4187/respcare.11298

Biochem Cell Biol. 2025 Jan 1;103:1-7. doi: 10.1139/bcb-2024-0221.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with high mortality and limited treatment options. While single-dose bleomycin-induced models are commonly used to investigate the pathogenesis of IPF, they fail to adequately replicate the complex pathological features in human patients, thereby hindering comprehensive investigations. Previous studies utilizing repetitive bleomycin injections have demonstrated a closer resemblance to human IPF pathology; however, the time- and resource-intensive nature of this approach presents significant drawbacks. Here, we propose a novel methodology involving twice-repeated oropharyngeal administration of bleomycin in mice, which closely mirrors the pathological manifestations observed in IPF patients. This model exhibited the honeycomb-like cyst formation, fibroblastic foci, bronchiolization of alveolar epithelium, emergence of metaplastic alveolar KRT5+ basal cells, and sustainability of these fibrotic phenotypes, thereby providing a robust model for IPF. Our findings establish a more efficient and translatable preclinical platform for investigating IPF pathogenesis and exploring potential therapeutic strategies.

PMID:39878201 | DOI:10.1139/bcb-2024-0221

HGG Adv. 2025 Jan 27:100410. doi: 10.1016/j.xhgg.2025.100410. Online ahead of print.

ABSTRACT

Most genetic variants identified through genome-wide association studies (GWAS) are suspected to be regulatory in nature, but only a small fraction colocalize with expression quantitative trait loci (eQTLs, variants associated with expression of a gene). Therefore, it is hypothesized but largely untested that integration of disease GWAS with context-specific eQTLs will reveal the underlying genes driving disease associations. We used colocalization and transcriptomic analyses to identify shared genetic variants and likely causal genes associated with critically ill COVID-19 and idiopathic pulmonary fibrosis. We first identified five genome-wide significant variants associated with both diseases. Four of the variants did not demonstrate clear colocalization between GWAS and healthy lung eQTL signals. Instead, two of the four variants colocalized only in cell-type and disease-specific eQTL datasets. These analyses pointed to higher ATP11A expression from the C allele of rs12585036, in monocytes and in lung tissue from primarily smokers, which increased risk of IPF and decreased risk of critically ill COVID-19. We also found lower DPP9 expression (and higher methylation at a specific CpG) from the G allele of rs12610495, acting in fibroblasts and in IPF lungs, and increased risk of IPF and critically ill COVID-19. We further found differential expression of the identified causal genes in diseased lungs when compared to non-diseased lungs, specifically in epithelial and immune cell types. These findings highlight the power of integrating GWAS, context-specific eQTLs, and transcriptomics of diseased tissue to harness human genetic variation to identify causal genes and where they function during multiple diseases.

PMID:39876559 | DOI:10.1016/j.xhgg.2025.100410

J Occup Environ Med. 2025 Jan 22. doi: 10.1097/JOM.0000000000003324. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to share the process of epidemiologic survey and demonstrate the decisive factors for evaluating work-related Idiopathic interstitial pneumonias (IIPs) in Korea.

METHODS: Data and reports of epidemiologic surveys were investigated and completed during 2010-2022.

RESULTS: A total of 228 idiopathic pulmonary fibrosis (IPF) cases requested for an epidemiologic survey, of which 153 (67.1%) were work-related. The level of exposure intensity was more than intermediate and the exposure duration was more than 10 years in the work-related IPF, so the decisive factors for work-related IPF were exposure substances, intensity and duration.The main factors for work-related acute interstitial pneumonia or cryptogenic organising pneumonia were exposure latency and exposure intensity.

CONCLUSIONS: The results of this study indicated the process of the epidemiologic survey and important factors for evaluating work-related IIPs.

PMID:39875335 | DOI:10.1097/JOM.0000000000003324

Front Immunol. 2025 Jan 13;15:1479458. doi: 10.3389/fimmu.2024.1479458. eCollection 2024.

ABSTRACT

INTRODUCTION: Diffuse parenchymal lung diseases (DPLD) cover heterogeneous types of lung disorders. Among many pathological phenotypes, pulmonary fibrosis is the most devastating and represents a characteristic sign of idiopathic pulmonary fibrosis (IPF). Despite a poor prognosis brought by pulmonary fibrosis, there are no specific diagnostic biomarkers for the initial development of this fatal condition. The major hallmark of lung fibrosis is uncontrolled activation of lung fibroblasts to myofibroblasts associated with extracellular matrix deposition and the loss of both lung structure and function.

METHODS: Here, we used this peculiar feature in order to identify specific biomarkers of pulmonary fibrosis in bronchoalveolar lavage fluids (BALF). The primary MRC-5 human fibroblasts were activated with BALF collected from patients with clinically diagnosed lung fibrosis; the activated fibroblasts were then washed rigorously, and further incubated to allow secretion. Afterwards, the secretomes were analysed by mass spectrometry.

RESULTS: In this way, the CD44 protein was identified; consequently, BALF of all DPLD patients were positively tested for the presence of CD44 by ELISA. Finally, biochemical and biophysical characterizations revealed an exosomal origin of CD44. Receiver operating characteristics curve analysis confirmed CD44 in BALF as a specific and reliable biomarker of IPF and other types of DPLD accompanied with pulmonary fibrosis.

PMID:39872532 | PMC:PMC11769834 | DOI:10.3389/fimmu.2024.1479458

Respir Med Case Rep. 2025 Jan 2;53:102165. doi: 10.1016/j.rmcr.2025.102165. eCollection 2025.

ABSTRACT

BACKGROUND: Anti-Ku antibodies are autoantibodies directed against the Ku protein complex involved in DNA repair. They are typically associated with overlap syndromes featuring polymyositis and systemic sclerosis. Isolated pulmonary involvement without myositis is exceedingly rare.

CASE PRESENTATION: We report the case of a 70-year-old male, a former smoker with an 18-year smoking history who quit 20 years ago, presenting with a one-year history of progressive dyspnea and dry cough. High-resolution computed tomography (HRCT) revealed pulmonary fibrosis with areas of ground-glass opacities. Laboratory tests showed antinuclear antibodies at a titer of 1:2560 with a speckled pattern and positivity for anti-Ku antibodies. Creatine phosphokinase levels were within normal limits. There were no clinical signs of myositis, myalgia, skin manifestations, or Raynaud's phenomenon.

CONCLUSION: This case underscores the rarity of pulmonary fibrosis as the sole clinical manifestation associated with anti-Ku antibody positivity in the absence of myositis. Clinicians should consider testing for anti-Ku antibodies in patients with idiopathic interstitial lung disease, even when muscular and cutaneous symptoms are absent.

PMID:39867941 | PMC:PMC11759561 | DOI:10.1016/j.rmcr.2025.102165

Cureus. 2024 Dec 27;16(12):e76454. doi: 10.7759/cureus.76454. eCollection 2024 Dec.

ABSTRACT

Background Interstitial lung diseases (ILDs) are a group of non-infectious diseases characterized by interstitial inflammation and fibrosis on histological examination. Gastroesophageal reflux disease (GERD) is common in this patient population, but whether there is a causal or coincidental relationship is not yet clear. It still remains unsettled how to diagnose GERD, and the role of different treatment modalities for GERD, in these lung disorders. Furthermore, most of the work is done to find the association of GERD with idiopathic pulmonary fibrosis (IPF) only. The aim of this study was to determine the prevalence of GERD in ILD patients presenting to an ILD clinic. Methods Prospective study of registered ILD patients during a period of eight months (May-December 2016). Diagnosis of GERD was made on a clinical basis (presentation with typical symptoms of heartburn and regurgitation). Current use of acid-reducing medications and steroids was also recorded. Results A total of 79 patients were included in the study. Females (58, 73.41%) outnumbered males (21, 26.58%). The heaviest burden of ILD was contributed by IPF (32, 40.50%), followed by non-specific interstitial pneumonia (NSIP) (26, 32.91%), hypersensitivity pneumonitis (HP) (8, 10.12%), sarcoidosis (5, 6.3%), silicosis (3, 3.8%), desquamative interstitial pneumonia (DIP) (2, 2.5%), and Langerhans cell histiocytosis (LCH) (3, 3.79%). Fifty (63.29%) patients were on steroids, and 29 (36.70%) were already taking anti-reflux medications at presentation. GERD was reported in 21 (65.6%) IPF, 12 (46.15%) NSIP, one (12.5%) HP, one (33.3%) silicosis, two (40%) sarcoidosis, and all (2,100%) of DIP patients. The overall prevalence of GERD was 39 (49.36%) in ILD patients. Conclusion The prevalence of abnormal acid reflux in ILD patients is high. It may be one of the underlying etiologies of lung fibrosis. Long-term follow-up is necessary to determine if control of reflux alters the natural history of these lung disorders. GERD must be investigated and managed optimally for patients with ILD.

PMID:39866988 | PMC:PMC11769694 | DOI:10.7759/cureus.76454

Heliyon. 2025 Jan 2;11(1):e41628. doi: 10.1016/j.heliyon.2025.e41628. eCollection 2025 Jan 15.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. It is characterized by inflammation and fibrosis in the lung parenchyma and interstitium. Given its poor prognosis and limited treatment options, understanding the underlying molecular mechanisms is crucial. Recent evidence suggests that lipid metabolism plays a pivotal role in IPF pathogenesis, however, the precise mechanisms remain poorly understood. To address this, we analyzed 12 bulk RNA-seq and 2 single-cell RNA-seq datasets from the GEO database using machine learning approaches. As a result, we identified four key lipid-related genes-PPARG, SPP1, CASP3, and PECAM1-that are expressed across various cell types. Specifically, in alveolar macrophages (AMs), we observed that PPARG was significantly downregulated, while SPP1 was highly expressed. Importantly, PPARG serves as a transcriptional regulator of SPP1, which in turn mediates intercellular signaling via CD44. Based on these findings, we propose a novel PPARG/SPP1/CD44 signaling pathway in AMs, which modulates lipid metabolism and likely contributes to the progression of fibrosis in IPF. Moreover, network pharmacology analysis identified several herbal compounds that target PPARG, offering potential therapeutic opportunities. In conclusion, these findings highlight the critical role of lipid metabolism in IPF and present novel molecular targets for the development of future therapeutic strategies.

PMID:39866448 | PMC:PMC11761845 | DOI:10.1016/j.heliyon.2025.e41628

Life (Basel). 2025 Jan 16;15(1):106. doi: 10.3390/life15010106.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with a median survival of 3-5 years. Antifibrotic therapies like pirfenidone and nintedanib slow progression, but the outcomes vary. Gender may influence disease presentation, progression, and response to treatment. This study evaluates the impact of gender on the 5-year survival, pharmacological management, and clinical outcomes of patients with IPF.

METHODS: A retrospective cohort study of 254 IPF patients was conducted, with 164 (131 males:33 females) having complete data. Patients underwent spirometry, DLCO, and 6 min walk tests. Data on comorbidities, smoking, antifibrotic therapy type, dosage adjustments, and adverse events were collected. We used Kaplan-Meier survival curves and logistic regression to assess gender-related differences in outcomes.

RESULTS: Men had worse lung function at diagnosis (FVC 74.9 ± 18.5 vs. 87.2 ± 20.1% of pred.; p < 0.001) and a higher smoking prevalence (74% vs. 30%; p < 0.001). Women had better survival (51.2 vs. 40.8 ± 19.2 months; p = 0.005) despite more frequent biopsy use (36% vs. 17%; p = 0.013). Women tolerated longer therapy better (p = 0.001). No differences were found between patients receiving reduced antifibrotic dosing and those receiving full dosing.

CONCLUSIONS: Gender has a significant impact on IPF outcomes, with women demonstrating better survival and tolerance to long-term therapy. In contrast, reducing antifibrotic treatment does not appear to significantly affect survival outcomes. These findings underscore the need for future research on gender-specific management approaches.

PMID:39860046 | DOI:10.3390/life15010106

Biomolecules. 2025 Jan 14;15(1):122. doi: 10.3390/biom15010122.

ABSTRACT

Diffuse interstitial lung diseases (ILD) include conditions with identifiable causes such as chronic eosinophilic pneumonia (CEP), sarcoidosis (SAR), chronic hypersensitivity pneumonitis (CHP), and connective tissue disease-associated interstitial pneumonia (CTD), as well as idiopathic interstitial pneumonia (IIP) of unknown origin. In non-IIP diffuse lung diseases, bronchoalveolar lavage (BAL) fluid appearance is diagnostic. This study examines lymphocyte subsets in BAL fluid and peripheral blood of 56 patients with diffuse ILD, excluding idiopathic pulmonary fibrosis (IPF), who underwent BAL for diagnostic purposes. Patients were classified into CEP, SAR, CHP, CTD, and IIP groups, and clinical data, BAL cell analysis, and peripheral blood mononuclear cell analysis were compared. Eosinophils and type 3 innate lymphocytes (ILC3s) were significantly increased in the BAL fluid of the CEP group. Receiver operating characteristic curve analysis identified eosinophils ≥ 8% in BAL cells and ILC3s ≥ 0.0176% in the BAL lymphocyte fraction as thresholds distinguishing CEP. SAR patients exhibited significantly elevated CD4/CD8 ratios in the BAL fluid, with a ratio of 3.95 or higher and type 1 innate lymphoid cell frequency ≥ 0.254% as differentiation markers. High Th1 cell frequency (≥17.4%) in BAL lymphocytes in IIP, elevated serum KL-6 (≥2081 U/mL) and SP-D (≥261 ng/mL) in CHP, and increased BAL neutrophils (≥2.0%) or a low CD4/CD8 ratio (≤1.2) in CTD serve as distinguishing markers for each ILD. Excluding CEP and SAR, CD4+ T cell frequencies, including Th1, Th17, and Treg cells in peripheral blood, may differentiate IIP, CHP, and CTD.

PMID:39858516 | DOI:10.3390/biom15010122

Pneumonia (Nathan). 2025 Jan 25;17(1):2. doi: 10.1186/s41479-024-00155-7.

ABSTRACT

BACKGROUND: A growing body of evidence suggests that prolonged use of inhaled corticosteroids (ICS) and proton pump inhibitors (PPIs) is associated with increased risks of pneumonia. A substantial proportion of people with idiopathic pulmonary fibrosis (IPF) are prescribed PPIs or ICS to treat common comorbidities, giving rise to concerns that use of these medications may be associated with potential harms in this patient population.

METHODS: We used UK Clinical Practice Research Datalink (CPRD) Aurum primary care data linked to national mortality and hospital admissions data to create a cohort of people diagnosed with IPF on or after 1 January 2010. Patients were assigned to one of three exposure categories according to their prescribing history in the 12 months prior to IPF diagnosis as follows: "regular" users (≥ 4 prescriptions), "irregular" users (1-3 prescriptions) and "non-users" (no prescriptions). We explored the association between PPI/ICS prescription and pneumonia hospitalisation and all-cause mortality using multinomial Cox regression models.

RESULTS: A total of 17,105 people met our study inclusion criteria; 62.6% were male and 15.9% were current smokers. Median age at IPF diagnosis was 76.7 years (IQR: 69.6-82.7). 19.9% were regularly prescribed PPIs, and 16.0% ICS, prior to IPF diagnosis. Regular prescribing of PPIs and ICS was positively associated with hospitalisation for pneumonia; the adjusted HR for pneumonia hospitalisation comparing regular PPI users with non-users was 1.14 (95%CI: 1.04-1.24); for regular ICS users the corresponding HR was 1.40 (95%CI: 1.25-1.55). We also observed a small increased risk for all-cause mortality in the "regular ICS user" group compared with the "non-user" control group (HRadj = 1.19, 1.06-1.33). We found no evidence of an association between PPI prescribing and all-cause mortality.

CONCLUSION: Prolonged prescription of medications used to treat common comorbidities in IPF may be associated with increased risks for severe respiratory infections. These findings point to a need to adopt an adequate risk-benefit balance approach to the prescribing of ICS-containing inhalers and PPIs in people with IPF without evidence of comorbidities, especially older patients and/or those with more advanced disease in whom respiratory infections are more likely to result in poorer outcomes.

PMID:39856755 | DOI:10.1186/s41479-024-00155-7

BMC Pulm Med. 2025 Jan 24;25(1):36. doi: 10.1186/s12890-025-03506-2.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common Interstitial Lung Disease (ILD). It is characterized by dyspnoea and a progressive decline in lung function, which negatively affects life. This study aimed to evaluate Health-Related Quality of Life (HRQoL) in IPF patients in Latin American countries.

METHODS: Six countries (Argentina, Bolivia, Colombia, Chile, Mexico, and the Dominican Republic) enrolled patients with IPF. They answered the Saint George's Respiratory Questionnaire for Idiopathic Pulmonary Fibrosis (SGRQ-I) and the Hospital Anxiety and Depression Scale (HADS). Demographic characteristics, the Torvan index, and a lung function test were also assessed. IPF was diagnosed according to the ATS/ERS/JRS/ALAT 2018 criteria.

RESULTS: We enlisted 75 patients diagnosed with IPF; 81% were male, with an average age of 74 ± 7. The total SGRQ-I score was 49 ± 23, with a higher score in the activity domain of 70 ± 23. Torvan index average was 17 ± 6. We found that 28% presented anxiety and 35% depression. Besides, we observed that patients requiring oxygen had a worse quality of life (total SGRQ-I 62 ± 22 vs. 45 ± 22, p = 0.003) without finding differences in antifibrotic therapy. We did not find differences in HRQoL when dividing groups according to their altitude above sea level, except for a higher frequency of anxiety in patients living at sea level.

CONCLUSIONS: We found similar data compared to those reported in real-life European populations. We also found that anxiety and depression are prevalent. However, they are often underdiagnosed and, therefore, left untreated.

PMID:39856586 | DOI:10.1186/s12890-025-03506-2

Gene. 2025 Jan 22:149271. doi: 10.1016/j.gene.2025.149271. Online ahead of print.

ABSTRACT

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal interstitial lung disease, characterized by excessive extracellular matrix (ECM) secretion that disrupts normal alveolar structure. This study aims to explore the potential molecular mechanisms underlying the promotion of IPF development.

METHODS: Firstly, we compared the transcriptome and single-cell sequencing data from lung tissue samples of patients with IPF and healthy individuals. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on the differentially expressed genes (DEGs). Furthermore, we employed sodium alginate hydrogels with varying degrees of crosslinking to provide differential mechanical stress, mimicking the mechanical microenvironment in vivo during lung fibrosis. On this basis, we examined cytoskeletal remodeling in fibroblasts MRC-5, mRNA expression of multiple related genes, immunofluorescence localization, and cellular proliferation capacity.

RESULTS: Bioinformatics analysis revealed a series of DEGs associated with IPF. Further functional and pathway enrichment analyses indicated that these DEGs were primarily enriched in ECM-related biological processes. Single-cell sequencing data revealed that fibroblasts and myofibroblasts are the main contributors to excessive ECM secretion and suggested activation of mechanotransduction and the Hippo/YAP signaling pathway in myofibroblasts. Cellular experiments demonstrated that sodium alginate hydrogels with different stiffness can simulate different mechanical stress environments, thereby affecting cytoskeletal rearrangement and Hippo/YAP pathway activity in MRC-5 lung fibroblasts. Notably, high levels of mechanical stress promoted YAP nuclear translocation, increased expression of type I collagen and α-SMA, and enhanced proliferative capacity. Additionally, we also found that fibroblasts primarily participate in mechanotransduction through the Rho/ROCK and Integrin/FAK pathways under high mechanical stress conditions, ultimately upregulating the gene expression of CCNE1/2, CTGF, and FGF1.

CONCLUSION: Our study uncovers the crucial role of cytoskeletal mechanotransduction in myofibroblast transformation and IPF development through activation of the Hippo/YAP pathway, providing new insights into understanding the pathogenesis of IPF.

PMID:39855369 | DOI:10.1016/j.gene.2025.149271