Am J Pathol. 2025 Jan 22:S0002-9440(25)00028-8. doi: 10.1016/j.ajpath.2024.12.015. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung disease have limited treatment options. Fibroblasts are key effector cells that sense matrix stiffness through conformation changes in mechanically sensitive receptors, leading to activation of downstream profibrotic pathways. Here we investigate the role of Piezo2, a mechanosensitive ion channel, in human and mouse lung fibrosis, and its function in myofibroblast differentiation in primary human lung fibroblasts (HLFs). Human samples from patients with IPF and mouse tissue from bleomycin induced pulmonary fibrosis was assessed. Primary HLFs from non-fibrotic donors were grown on substrates of different stiffness to induce myofibroblast differentiation and treated with a Piezo2 inhibitor. Piezo2 expression is upregulated in tissue from patients with IPF and in fibrotic mouse lung tissue. Additionally, interrogation of published single-cell RNAseq data showed that Piezo2 is expressed in the pro-fibrotic Cthrc1+ fibroblast subpopulation. Myofibroblast differentiation was increased in HLFs grown on substrates with fibrotic levels of stiffness compared to that seen in softer substrates. Piezo2 inhibition reduced stiffness-induced expression alpha smooth muscle actin and fibronectin in HLFs. Piezo2 expression is elevated in fibrotic lung disease in both patients and rodents and its presence is key in the differentiation of fibroblasts to the pro-fibrotic myofibroblasts. Blocking Piezo2 may play a key role in fibrosis and thus be a novel therapeutic approach to treat pulmonary fibrosis.

PMID:39855300 | DOI:10.1016/j.ajpath.2024.12.015

Medicine (Baltimore). 2025 Jan 24;104(4):e41320. doi: 10.1097/MD.0000000000041320.

ABSTRACT

While recent studies suggested a potential causal link between type 1 diabetes mellitus (T1DM) but not type 2 diabetes mellitus (T2DM) and idiopathic pulmonary fibrosis (IPF), the involved mechanism remains unclear. Here, using a Mendelian randomization (MR) approach, we verified the causal relationship between the two types of diabetes mellitus and IPF and investigated the possible role of inflammation in the association between diabetes mellitus and IPF. Based on genome-wide association study (GWAS) summary data of T1DM, T2DM, and IPF, the univariable MR, multivariable MR (MVMR), and mediation MR were successively used to analyze the causal relationship. Inverse variance weighted was used as the main method to infer the causal effect, together with a series of sensitivity analyses. The univariable MR showed that only T1DM increased the risk of IPF, and there was no significant causal relationship between T2DM and IPF. The MVMR further verified that there was an independent direct causal effect of T1DM on IPF. Further mediation analysis showed that this effect was partly mediated by increasing C-X-C motif chemokine ligand 10 (CXCL10) and interleukin-12 subunit beta (IL-12B). In conclusion, T1DM is related to an increased risk of IPF. Notably, the causal effect was partially mediated by CXCL10 and IL-12B. Hence, monitoring T1DM patients may help in the early detection and prevention of IPF.

PMID:39854757 | DOI:10.1097/MD.0000000000041320

Sports (Basel). 2025 Jan 8;13(1):9. doi: 10.3390/sports13010009.

ABSTRACT

Chronic lung diseases such as Chronic Obstructive Pulmonary Disease, Interstitial Lung Disease (ILD), and Pulmonary Hypertension (PH) are characterized by progressive symptoms such as dyspnea, fatigue, and muscle weakness, often leading to physical inactivity, and reduced quality of life. Many patients also experience significantly impaired exercise tolerance. While pulmonary, cardiovascular, respiratory, and peripheral muscle dysfunction contribute to exercise limitations, recent evidence suggests that hypoxia and impairments in cerebral oxygenation may also play a role in exercise intolerance. This narrative review (i) summarizes studies investigating cerebral oxygenation responses during exercise in patients with different types of chronic lung diseases and (ii) discusses possible mechanisms behind the blunted cerebral oxygenation during exercise reported in many of these conditions; however, the extent of cerebral desaturation and the intensity at which it occurs can vary. These differences depend on the specific pathophysiology of the lung disease and the presence of comorbidities. Notably, reduced cerebral oxygenation during exercise in fibrotic-ILD has been linked with the development of dyspnea and early exercise termination. Understanding the effects of chronic lung disease on cerebral oxygenation during exercise may improve our understanding of exercise intolerance mechanisms and help identify therapeutic strategies to enhance brain health and exercise capacity in these patients.

PMID:39852605 | DOI:10.3390/sports13010009

J Med Case Rep. 2025 Jan 23;19(1):32. doi: 10.1186/s13256-025-05031-6.

ABSTRACT

BACKGROUND: Dyskeratosis congenita is a rare genetic disease due to telomere biology disorder and characterized by heterogeneous clinical manifestations and severe complications. "Porto-sinusoidal vascular disease" has been recently proposed, according to new diagnostic criteria, to replace the term "idiopathic non-cirrhotic portal hypertension." TERT plays an important role in telomeric DNA repair and replication. A TERT c.2286 + 1G/A mutation in a splicing consensus site was identified in a patient with pulmonary fibrosis. Recently, a pathogenic de novo TERT c.280A > T variant was associated with diffuse lung disease in an infant.

CASE PRESENTATION: A 16-year-old Han male patient experienced unexplained black stool for 7 days, accompanied by dizziness and fatigue. On examination, there were mesh pigmentations on the exposed areas of the skin on both hands and feet. Laboratory testing revealed moderate hemorrhagic anemia and mild elevation of alanine aminotransferase. A computed tomography scan showed portal hypertension, esophageal and gastric varices, and splenomegaly. The liver stiffness measurement by FibroScan was 6.0 kPa. Liver biopsy revealed typical features of porto-sinusoidal vascular disease. Whole exome sequencing identified a heterozygous TERT c.2286 + 1G > A de novo mutation and quantitative polymerase chain reaction revealed very short telomeres (less than the first percentile for his age). The patient was diagnosed as TERT de novo mutation-related dyskeratosis congenita and porto-sinusoidal vascular disease. He underwent esophageal and gastric variceal ligation treatment and received a carvedilol tablet (12.5 mg) every morning. After 6 months, he has moderate iron deficiency anemia and has started receiving polysaccharide iron complex therapy.

CONCLUSION: When discovering reticular rash and unknown portal hypertension, it is necessary to perform whole exome sequencing and chromosome length testing to clarify the possibility of dyskeratosis congenita/telomere biology disorder with porto-sinusoidal vascular disease.

PMID:39849589 | DOI:10.1186/s13256-025-05031-6

Sci Rep. 2025 Jan 23;15(1):3007. doi: 10.1038/s41598-025-87474-x.

ABSTRACT

The traditional Chinese medicine compound preparation known as Jinbei Oral Liquid (JBOL) consists of 12 herbs, including Astragalus membranaceus (Fisch.) Bge, Codonopsis pilosula (Franch.) Nannf, et al. Having been used for over 30 years in the treatment of pulmonary diseases, JBOL was evaluated in this study in order to assess its effect on idiopathic pulmonary fibrosis as well as its safety (ChiCTR2000035351, Chictr.org.cn.09/08/2020). A double-blind, multicenter, randomized, proof-of-concept trial was conducted to assess the efficacy of oral JBOL 40 ml and Corbrin Capsules 1 g compared to a placebo and Corbrin Capsules in patients with idiopathic pulmonary fibrosis (IPF). Over a 26-week period, patients received the active treatment or placebo three times daily, in a 1:1 ratio. This clinical study uses a randomized method, with a cycle of every 4 patients. TCM doctors at or above the deputy director level of the research center conduct TCM dialectics on IPF patients. To assess efficacy, over the duration of the trial, we measured serial changes in a composite indicator encompassing time to first acute exacerbation of IPF (first hospitalization or death due to respiratory cause), total lung capacity (TLC) (mL), predicted forced vital capacity (FVC%), forced vital capacity (FVC) (mL), predicted diffusing capacity of the lungs for carbon monoxide (predicted DLco%), 6-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) total score, and arterial oxygen partial pressure (PaO2) from baseline to week 26 versus placebo. A total of 103 patients were screened, and 72 received the study medication. Of these, 68 patients were included in the analysis set, with 34 receiving JBOL and 34 receiving a placebo. After 26 weeks, a statistically significant reduction in total lung capacity (TLC) was observed for the JBOL group, with a change of 136 mL compared to -523 mL for the placebo group (difference 659 mL, 95% CI -1215 to -104 mL, p = 0.02). The study found that the change in FVC% predicted was - 1.48% and - 3.58% for the JBOL and placebo groups, respectively (difference of 2.10%, 95% CI -7.13 to 2.93, p = 0.41). Additionally the differences between the two groups in changes in FVC (mL), DLCO % predicted, PaO2 (mmHg) measures were - 67 mL (95% CI -238 to 104), -7.74% (95% CI -17.26 to 1.79), and - 3.57 mmHg (95% CI -10.02 to 2.87), respectively. Treatment with JBOL compared to placebo resulted in sequential changes in acute exacerbation, with no significant difference in SGRQ scores. It was not found that there was a statistically significant difference between the JBOL and placebo groups in TEAE reporting and serious TEAE reporting. Compared to the placebo group, there was a statistically significant reduction (p < 0.021) in TLC (mL) after 26 weeks for JBOL. The rates of FVC % predicted, FVC, DLCO % predicted, and PaO2 in the group treatment with JBOL were numerically lower than those in the placebo treatment group, although these differences did not reach statistical significance. JBOL exhibited comparable safety to placebo. This study has preliminarily shown the efficacy and safety of JBOL for IPF, but this is an exploratory clinical trial, more patient-involved studies should be needed in the near future.Trial registration: Chictr.org.cn ChiCTR2000035351; the trial was prospective clinical studies registered on August 9, 2020.

PMID:39849152 | DOI:10.1038/s41598-025-87474-x

Thorax. 2025 Jan 22:thorax-2024-222754. doi: 10.1136/thorax-2024-222754. Online ahead of print.

NO ABSTRACT

PMID:39848685 | DOI:10.1136/thorax-2024-222754

Int J Biochem Cell Biol. 2025 Jan 21:106739. doi: 10.1016/j.biocel.2025.106739. Online ahead of print.

ABSTRACT

Lung fibrosis, including idiopathic pulmonary fibrosis (IPF), is a complex and devastating disease characterised by the progressive scarring of lung tissue leading to compromised respiratory function. Aberrantly activated fibroblasts deposit extracellular matrix components into the surrounding lung tissue, impairing lung function and capacity for gas exchange. Both genetic and epigenetic factors have been found to play a role in the pathogenesis of lung fibrosis, with emerging evidence highlighting the interplay between these two regulatory mechanisms. This review provides an overview of the current understanding of the interplay between genetics and epigenetics in lung fibrosis. We discuss the genetic variants associated with susceptibility to lung fibrosis and explore how epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNA expression contribute to disease. Insights from genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) are integrated to explore the molecular mechanisms underlying lung fibrosis pathogenesis. We also discuss the potential clinical implications of genetics and epigenetics in lung fibrosis, including the development of novel therapeutic targets. Overall, this review highlights the importance of considering both genetic and epigenetic factors in the understanding and management of lung fibrosis.

PMID:39848439 | DOI:10.1016/j.biocel.2025.106739

Proteomes. 2025 Jan 13;13(1):3. doi: 10.3390/proteomes13010003.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by repetitive alveolar injuries with excessive deposition of extracellular matrix (ECM) proteins. A crucial need in understanding IPF pathogenesis is identifying cell types associated with histopathological regions, particularly local fibrosis centers known as fibroblast foci. To address this, we integrated published spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) transcriptomics and adopted the Query method and the Overlap method to determine cell type enrichments in histopathological regions. Distinct fibroblast cell types are highly associated with fibroblast foci, and transitional alveolar type 2 and aberrant KRT5-/KRT17+ (KRT: keratin) epithelial cells are associated with morphologically normal alveoli in human IPF lungs. Furthermore, we employed laser capture microdissection-directed mass spectrometry to profile proteins. By comparing with another published similar dataset, common differentially expressed proteins and enriched pathways related to ECM structure organization and collagen processing were identified in fibroblast foci. Importantly, cell type enrichment results from innovative spatial proteomics and scRNA-seq data integration accord with those from spatial transcriptomics and scRNA-seq data integration, supporting the capability and versatility of the entire approach. In summary, we integrated spatial multi-omics with scRNA-seq data to identify disease-associated cell types and potential targets for novel therapies in IPF intervention. The approach can be further applied to other disease areas characterized by spatial heterogeneity.

PMID:39846634 | DOI:10.3390/proteomes13010003

Front Immunol. 2025 Jan 8;15:1436491. doi: 10.3389/fimmu.2024.1436491. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease, characterized by impaired wound repair, tissue remodeling and fibrosis. Immune system may participate in the development and progression of the disease as indicated by altered activity in IPF sufferers. This study investigates the immune response to the BNT162b2 COVID-19 vaccine in patients with IPF compared to healthy controls, with a particular focus on evaluation of antibody responses, interferon-gamma release, cytokine profiling and a broad panel of immune cell subpopulations. IPF patients without prior exposure to SARS-CoV-2 had undetectable levels of anti-N IgG antibodies, highlighting their lack of previous infection. After vaccination, IPF patients showed a significant increase in anti-S1 IgG and IgA antibodies, though their levels were lower compared to healthy controls and convalescent IPF patients. Additionally, IPF patients exhibited altered proportions of regulatory T cells (Tregs) and effector T lymphocytes (Teffs) before and after vaccination. Specifically, IPF patients had higher percentages of Tregs with a Th2 phenotype and Th17 Tregs, along with reduced proportions of Th1/17 Tregs. Teffs in IPF patients showed a decrease in Th1-like and Th2-like populations after vaccination. Moreover, IPF patients demonstrated elevated populations of cytotoxic T lymphocytes (Tc) before vaccination and increased levels of γδ Tc cells throughout the study. Alterations in cytokine profiles were also observed, IPF patients showed higher levels of IL-6 and IL-22 compared to healthy controls. These findings suggest a distinct immune response in IPF patients to the COVID-19 vaccine, characterized by differences in antibody production, T cell differentiation and cytokine secretion compared to healthy individuals.

PMID:39845961 | PMC:PMC11750670 | DOI:10.3389/fimmu.2024.1436491

Respir Res. 2025 Jan 22;26(1):34. doi: 10.1186/s12931-025-03107-x.

ABSTRACT

Progressive forms of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), are deadly disorders lacking non-invasive biomarkers for assessment of early disease activity, which presents a major obstacle in disease management. Excessive extracellular matrix (ECM) deposition is a hallmark of these disorders, with fibronectin being an abundant ECM glycoprotein that is highly upregulated in early fibrosis and serves as a scaffold for the deposition of other matrix proteins. Due to its role in active fibrosis, we are targeting fibronectin as a biomarker of early lung fibrosis disease activity via the PEGylated fibronectin-binding polypeptide (PEG-FUD). In this work, we demonstrate the binding of PEG-FUD to the fibrotic lung throughout the course of bleomycin-induced murine model of pulmonary fibrosis. We first analyzed the binding of radiolabeled PEG-FUD following direct incubation to precision cut lung slices from mice at different stages of experimental lung fibrosis. Then, we administered fluorescently labeled PEG-FUD subcutaneously to mice over the course of bleomycin-induced pulmonary fibrosis and assessed peptide uptake 24 h later through ex vivo tissue imaging. Using both methods, we found that peptide targeting to the fibrotic lung is increased during the fibrogenic phase of the single dose bleomycin lung fibrosis model (days 7 and 14 post-bleomycin). At these timepoints we found a correlative relationship between peptide uptake and fibrotic burden. These data suggest that PEG-FUD targets fibronectin associated with active fibrogenesis in this model, making it a promising candidate for a clinically translatable molecular imaging probe to non-invasively determine pulmonary fibrosis disease activity, enabling accelerated therapeutic decision-making.

PMID:39844185 | DOI:10.1186/s12931-025-03107-x

Eur Respir Rev. 2025 Jan 22;34(175):240133. doi: 10.1183/16000617.0133-2024. Print 2025 Jan.

ABSTRACT

INTRODUCTION: People with idiopathic pulmonary fibrosis (IPF) and other forms of progressive pulmonary fibrosis (PPF) have a high symptom burden and a poor health-related quality of life (HRQoL). Despite efforts to offer specialised treatment, clinical care for these patients remains suboptimal and several nonmedical needs remain unaddressed. Developing a core outcome set (COS) can help to identify a minimum set of agreed-upon outcomes that should be measured and acted-upon in clinical care.

AIM: As a first step towards developing a COS for IPF/PPF, we aimed to identify outcome domains investigated in IPF/PPF research.

METHODS: Conducted within the COCOS-IPF (Co-designing a Core Outcome Set for and with patients with IPF) project, this scoping review follows Joanna Briggs Institute methodology and PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines to search PubMed, Embase and Web of Science for quantitative, qualitative and mixed-methods papers. We extracted each paper's outcomes verbatim and classified them using the COMET (Core Outcome Measures in Effectiveness Trials) taxonomy. Then, the research team structured outcomes or concepts with similar meanings inductively into outcome domains.

RESULTS: We included 428 papers, extracting 1685 outcomes. Most outcomes (n=1340) were identified in quantitative sources, which we could classify in 64 outcome domains, with the main domains being "all-cause survival" (n=237), "lung function" (n=164) and "exercise capacity" (n=99). Qualitative sources identified 51 outcome domains, with the most frequent being "capability to do activities you enjoy" (n=31), "anxiety, worry and fear" (n=26) and "dealing with disease progression" (n=25).

CONCLUSIONS: The identified outcomes, spanning diverse domains, highlight the complexity of patient experiences and can form the basis to develop a COS for IPF/PPF clinical care, as well as future research.

PMID:39843158 | DOI:10.1183/16000617.0133-2024

BMJ Case Rep. 2025 Jan 21;18(1):e263676. doi: 10.1136/bcr-2024-263676.

ABSTRACT

A woman in her mid-70s presented with worsening dyspnoea, cough and fatigue initially treated for pneumonia. Despite antibiotics, her condition deteriorated, prompting further investigation. Medical history included previous breast implants, the latter of which had ruptured years earlier and was subsequently removed prior to the current presentation. Imaging revealed bilateral lung consolidations and lymphadenopathy. Bronchoalveolar lavage indicated macrophagic alveolitis, while biopsies showed chronic inflammation and the presence of silicone. Diagnosis of chronic pulmonary silicone embolism was made, a rare condition linked to the migration of silicone particles into the lungs, causing inflammation. Treatment involved corticosteroids, leading to symptom resolution. This case highlights the diagnostic challenges of silicone pneumonitis, which can manifest years after implant rupture and removal. Clinicians should be aware of this condition to avoid misdiagnosis and delayed treatment, as symptoms may persist even after implant removal due to irreversible lung fibrosis.

PMID:39842899 | DOI:10.1136/bcr-2024-263676

Pneumologie. 2025 Jan 22. doi: 10.1055/a-2512-8349. Online ahead of print.

ABSTRACT

Patients with interstitial lung disease (ILD) and especially with idiopathic pulmonary fibrosis(IPF) suffer from reduced survival expectation and risk of exacerbations. Lung cancer is a relevant comorbidity in ILD patients and associated with impaired survival.The most frequent ILD among patients with NSCLC (Non-small cell lung cancer) is idiopathic pulmonary fibrosis (IPF), which is associated with an greater decline in lung function and a higher risk of death.The prevalence of lung cancer in patients with ILD is up to 10% and in autopsy studies a prevalence up to 48% has been found.There are no guidelines for patients with lung cancer and ILD. Moreover, no adequate evidence is available.Therefore, we reviewed currently available literature to present an overview of the state of the art.In this review we focus on staging and treatment of the comorbidity of lung cancer and ILD.

PMID:39842452 | DOI:10.1055/a-2512-8349

Lung. 2025 Jan 22;203(1):27. doi: 10.1007/s00408-024-00783-2.

ABSTRACT

PURPOSE: Pulmonary hypertension (PH) is associated with morbidity and mortality in patients with interstitial lung disease (ILD). Several prediction models have been proposed to predict PH in ILD patients. We sought to discern how previously described prediction models perform in predicting PH in patients with ILD.

METHODS: Patients with ILD who completed a baseline right heart catheterization, from Inova Fairfax Hospital, Northwestern Memorial Hospital, and Asan Medical Center in Korea were enrolled. The performance of various prediction models (FORD model, the FORD calculator, the PH-ILD Detection tool, and the mean pulmonary artery pressure prediction model) were assessed using receiver operating characteristic (ROC) curves and area under the receiver operating characteristic curve (AUROC). There were four definitions of pulmonary hypertension against which the models were evaluated.

RESULTS: There were a total of 192 patients with ILD, of whom 32.8% (n = 63/192) met the modified 5th world symposium on PH definition of precapillary PH. Among the models assessed, the FORD calculator had an AUROC (0.733) that was marginally highest. Subgroup analysis revealed that the FORD index had the highest AUROC (0.817) in patients with idiopathic pulmonary fibrosis, while the FORD calculator had the highest AUROC (0.751) in patients with non-IPF ILD.

CONCLUSION: The FORD model can be used to predict group 3 PH in both IPF patients and non-IPF ILD patients. It could serve as a tool for ILD patient selection for right heart catheterization as well as an enrichment tool for clinical trials targeting the pulmonary vasculature.

PMID:39841267 | DOI:10.1007/s00408-024-00783-2

BMC Med. 2025 Jan 21;23(1):22. doi: 10.1186/s12916-025-03848-y.

ABSTRACT

BACKGROUND: Current research underscores the need to better understand the pathogenic mechanisms and treatment strategies for idiopathic pulmonary fibrosis (IPF). This study aimed to identify key targets involved in the progression of IPF.

METHODS: We employed Mendelian randomization (MR) with three genome-wide association studies and four quantitative trait loci datasets to identify key driver genes for IPF. Prioritized targets were evaluated for respiratory insufficiency and transplant-free survival. The therapeutic efficacy of the core gene was validated in cellular and animal models. Additionally, we conducted a comprehensive evaluation of therapeutic value, pathogenic mechanisms, and safety through phenome-wide association study (PheWAS), mediation analysis, transcriptomic analyses, shared causal variant exploration, DNA methylation MR, and protein interactions.

RESULTS: Multiple MR results revealed that BRSK2 has a significant pathogenic impact on IPF at both transcriptional and translational levels, with a lung tissue-specific association (OR = 1.596; CI, 1.300-1.961; Pval = 8.290 × 10 - 6). BRSK2 was associated with IPF progression driven by high-risk factors, with mediation effects ranging from 34.452 to 69.665%. Elevated BRSK2 expression in peripheral blood mononuclear cells correlated with reduced pulmonary function, while increased circulating BRSK2 levels suggested respiratory failure and shorter transplant-free survival in IPF patients. BRSK2 silencing attenuated lung fibrosis progression in cellular and animal models. Transcriptomic integration identified PSMB1, CTSD, and CTSH as significant downstream effectors of BRSK2, with PSMB1 showing robust shared causal variant support (PPH4 = 0.800). Colocalization analysis and phenotype scan deepened the pathogenic association of BRSK2 with IPF, while methylation MR analysis highlighted the critical role of epigenetic regulation in BRSK2-driven IPF pathogenesis. PheWAS revealed no significant drug-related toxicities for BRSK2, and its therapeutic potential was further underscored by protein interaction analyses.

CONCLUSIONS: BRSK2 is identified as a critical pathogenic factor in IPF, with strong potential as a therapeutic target. Future studies should focus on its translational implications and the development of targeted therapies to improve patient outcomes.

PMID:39838395 | DOI:10.1186/s12916-025-03848-y

Sci Total Environ. 2025 Jan 20;964:178409. doi: 10.1016/j.scitotenv.2025.178409. Online ahead of print.

ABSTRACT

Air pollution has been associated with a higher incidence of idiopathic pulmonary fibrosis (IPF), yet this metabolic mechanism remains unclear. 185,865 participants were included in the UK Biobank. We estimated air pollution exposure using the bilinear interpolation approach, including fine particle matter with diameter < 2.5 μm (PM2.5), particle matter with diameter < 10 μm (PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx). We identified metabolites and established the metabolic signature with air pollutants using an elastic net regularized regression. Cox proportional hazards models combined with generalized propensity score (GPS) were conducted to evaluate the relationships between metabolic signatures and incident IPF, and mediation analysis was performed to evaluate potential mediators. During a median follow-up of 12.3 years, 1239 IPF cases were ascertained. We identified multi-metabolite profiles comprising 87 metabolites for PM2.5, 65 metabolites for PM10, 71 metabolites for NO2, and 76 metabolites for NOx. Metabolic signatures were associated with incident IPF, with HRs of 1.20 (95 % CI: 1.13, 1.27), 1.09 (95 % CI: 1.03, 1.15), 1.23 (95 % CI: 1.16, 1.31), and 1.24 (95 % CI: 1.17, 1.31) per standard deviation (SD) increase in metabolic profiles associated with PM2.5, PM10, NO2, and NOx, respectively. Furthermore, metabolic signatures of PM2.5, PM10, NO2 and NOx significantly mediated 5.71 %, 3.98 %, 4.21 %, and 4.58 % of air pollution on IPF. Long-term air pollution was associated with a higher risk of IPF, with metabolites potentially playing a mediating role. The findings emphasize the significance of improving metabolic status for the prevention of IPF.

PMID:39837121 | DOI:10.1016/j.scitotenv.2025.178409

Anal Methods. 2025 Jan 21. doi: 10.1039/d4ay01599a. Online ahead of print.

ABSTRACT

The study aims to evaluate and compare two advanced proteomic techniques, nanoLC-MALDI-MS/MS and nanoLC-TIMS-MS/MS, in characterizing extracellular vesicles (EVs) from the bronchoalveolar lavage fluid (BALF) of patients with asthma and idiopathic pulmonary fibrosis (IPF). Pulmonary diseases, driven by pollutants and infections, often necessitate detailed analysis of BALF to identify diagnostic biomarkers and therapeutic targets. EVs, which include exosomes, microvesicles, and apoptotic bodies, are isolated using filtration and ultracentrifugation, and their morphology, concentration, and size distribution are assessed through transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The proteomic profiles of these EVs are then analyzed using the aforementioned techniques, highlighting their unique and common proteins. The study found that nanoLC-TIMS-MS/MS identified significantly more proteins compared to nanoLC-MALDI-MS/MS. Functional analysis via Gene Ontology revealed pathways related to inflammation and cell signaling, underscoring the role of EVs in disease pathophysiology. The findings suggest that EVs in BALF can serve as valuable biomarkers and therapeutic targets in respiratory diseases, providing a foundation for future research and clinical applications.

PMID:39835386 | DOI:10.1039/d4ay01599a

Front Med (Lausanne). 2025 Jan 6;11:1497530. doi: 10.3389/fmed.2024.1497530. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic inflammation and progressive fibrosis. The blood urea nitrogen-to-albumin ratio (BAR) is a comprehensive parameter associated with inflammation status; however, it is unknown whether the BAR can predict the prognosis of IPF.

METHODS: This retrospective study included 176 patients with IPF, and 1-year all-cause mortality of these patients was recorded. A receiver operating characteristic (ROC) curve was used to explore the diagnostic value of BAR for 1-year all-cause mortality in IPF patients, and the survival rate was further estimated using the Kaplan-Meier survival curve. Cox proportional hazards regression model and forest plot were used to assess the association between the BAR and 1-year all-cause mortality in IPF patients.

RESULTS: The BAR of IPF patients was significantly higher in the non-survivor group than in the survivor group [0.16 (0.13-0.23) vs. 0.12 (0.09-0.17) mmol/g, p = 0.002]. The area under the ROC curve for predicting 1-year all-cause mortality in IPF patients was 0.671, and the optimal cut-off value was 0.12 mmol/g. The Kaplan-Meier survival curve showed that the 1-year cumulative survival rate of IPF patients with a BAR ≥0.12 was significantly decreased compared with the patients with a BAR <0.12. The Cox regression model and forest plot showed that the BAR was an independent prognostic biomarker for 1-year all-cause mortality in IPF patients (HR = 2.778, 95% CI 1.020-7.563, p = 0.046).

CONCLUSION: The BAR is a significant predictor of 1-year all-cause mortality of IPF patients, and high BAR values may indicate poor clinical outcomes.

PMID:39835108 | PMC:PMC11743257 | DOI:10.3389/fmed.2024.1497530

Commun Biol. 2025 Jan 20;8(1):93. doi: 10.1038/s42003-025-07529-7.

ABSTRACT

Invasive lung myofibroblasts are the main cause of tissue remodeling in idiopathic pulmonary fibrosis (IPF). A key mechanism contributing to this important feature is aberrant crosstalk between the abnormal/injured lung epithelium and pulmonary fibroblasts. Here, we demonstrate that lungs from patients with IPF and from mice with bleomycin (BLM)-induced pulmonary fibrosis (PF) are characterized by the induction of human epididymis protein 4 (HE4) overexpression in epithelial cells. HE4 knockdown primarily in epithelial cells attenuates BLM-induced PF in mice, whereas the administration of recombinant mouse HE4 exacerbates fibrosis after BLM stimulation. Mechanistic analysis shows that HE4 and annexin II (ANXA2) specific binding enhances the profibrotic phenotype in epithelial cells, and directly promotes lung fibroblast activation, leading to aberrant epithelial-fibroblast crosstalk and the persistent myofibroblast phenotype. The HE4 and ANXA2 binding site is located after the 30th amino acid at the N terminus of the HE4 molecule. Finally, intratracheal administration of HE4 shRNA lentivirus protects mice against BLM-induced PF. These data suggest that HE4 can serve as a potential therapeutic target in the treatment of IPF.

PMID:39833358 | DOI:10.1038/s42003-025-07529-7

BMJ Open Respir Res. 2025 Jan 19;12(1):e002725. doi: 10.1136/bmjresp-2024-002725.

ABSTRACT

INTRODUCTION: Persistent lung abnormalities following COVID-19 infection are common. Similar parenchymal changes are observed in idiopathic pulmonary fibrosis (IPF). We investigated whether common genetic risk factors in IPF are associated with developing lung parenchymal abnormalities following severe COVID-19 disease.

METHODS: Consecutive adults hospitalised for laboratory-confirmed COVID-19 infection were prospectively recruited from March to May 2020. Three single-nucleotide polymorphisms (SNPs) conferring risk for IPF were genotyped (MUC5B rs35705950, ATP11A rs1278769 and DPP9 rs12610495). High-resolution CT and pulmonary function tests were performed at 3 months postdischarge from hospital. Ground glass opacities and reticulation on imaging were visually quantified by two expert thoracic radiologists. Linear regression was used to evaluate the association between risk alleles at each of the three SNPs and (a) lung parenchymal abnormalities as well as (b) pulmonary function, adjusted for age, sex, smoking history and days spent on supplemental oxygen during acute illness.

RESULTS: 71 patients were included. Mean age was 63±16 years, 62% were male, 31% were ever-smokers and median hospital length of stay was 9±11 days, with 23% requiring mechanical ventilation. The MUC5B risk allele was associated with a significant decrease in ground glass (β=-0.8, 95% CI -1.5 to -0.1, p=0.02) at 3 months, and this finding was paralleled by a concurrent but non-significant trend towards increased diffusion capacity for carbon monoxide (DLCO) (β=8.8, 95% CI -1.2 to 18.8, p=0.08) compared with patients without this risk allele. None of the risk alleles were significantly associated with reticulation at 3 months.

CONCLUSION: In an adjusted analysis controlling for severity of infection, MUC5B was associated with reduced ground glass and a trend towards concordant higher DLCO at 3 months after severe COVID-19 illness. This hypothesis-generating result suggests a possible protective effect of MUC5B in postinfectious lung abnormalities as compared with fibrosis in IPF, highlighting a plausible trade-off between its role in immune defence and epithelial cell function.

PMID:39832890 | DOI:10.1136/bmjresp-2024-002725