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

Sci Rep. 2025 Jan 17;15(1):2331. doi: 10.1038/s41598-025-86544-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disorder of unknown etiology, characterized by interstitial fibrosis of the lungs. Bleomycin-induced pulmonary fibrosis mouse model (BLM model) is a widely used animal model to evaluate therapeutic targets for IPF. Histopathological analysis of lung fibrosis is an important method for evaluating BLM model. However, this method requires expertise in recognizing complex visual patterns and is time-consuming, making the workflow difficult and inefficient. Therefore, we developed a new workflow for BLM model that reduces inter- and intra-observer variations and improves the evaluation process. We generated deep learning models for grading lung fibrosis that were able to achieve accuracy comparable to that of pathologists. These models incorporate complex image patterns and qualitative factors, such as collagen texture and distribution, potentially identifying drug candidates overlooked in evaluations based solely on simple area extraction. This deep learning-based fibrosis grade assessment has the potential to streamline drug development for pulmonary fibrosis by offering higher granularity and reproducibility in evaluating BLM model.

PMID:39833349 | DOI:10.1038/s41598-025-86544-4

J Thorac Dis. 2024 Dec 31;16(12):8379-8388. doi: 10.21037/jtd-24-1165. Epub 2024 Dec 11.

ABSTRACT

BACKGROUND: The benefits of pulmonary rehabilitation (PR) for patients with idiopathic pulmonary fibrosis (IPF) have been limited to improving dyspnea, exercise capacity, and quality of life (QoL). This study aimed to assess the current status of PR and its effect on prognosis.

METHODS: The Nationwide Korean Health Insurance Review and Assessment Service (HIRA) database was used in this study. Annual PR implementation rate since 2016 following its coverage in the health insurance was analyzed. IPF cases were defined using the International Classification of Diseases 10th Revision (ICD-10) codes and rare intractable diseases (RID) codes. Risk of acute exacerbation (AE) and mortality of IPF patients with or without PR were analyzed.

RESULTS: Of the 4,228 patients with IPF, only 205 (4.85%) received PR. Patients in the PR group were more frequently treated with pirfenidone and systemic steroids than non-PR group. In patients treated with steroids, mortality risk increased regardless of PR application, with hazard ratio (HR) of 1.63 [95% confidence interval (CI): 1.26-2.10, P<0.001] in the PR group and 1.38 (95% CI: 1.21-1.57, P<0.001) in the non-PR group, compared to those not treated with steroids. Additionally, PR did not significant affect mortality risk in patients not receiving steroids (HR, 1.49, 95% CI: 0.87-2.54, P=0.15). Similar patterns were seen for the risk of AE.

CONCLUSIONS: PR was applied in only a minority of patients with IPF. It did not succeed in reducing the risk of AE or mortality. A prospective study targeting early-stage patients is needed to evaluate the impact of PR considering the progressive nature of IPF disease itself.

PMID:39831231 | PMC:PMC11740027 | DOI:10.21037/jtd-24-1165

J Thorac Dis. 2024 Dec 31;16(12):8528-8537. doi: 10.21037/jtd-24-1356. Epub 2024 Dec 28.

ABSTRACT

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) are at risk of lung cancer development. Antifibrotic therapy could slow disease progression of IPF, but there is limited data on its effectiveness on lung cancer. Here, we aimed to investigate lung cancer incidence and the risk of mortality of patients with IPF receiving antifibrotic therapy.

METHODS: Data from the Korean National Health Insurance service database between October 2015 and September 2021 were used. The incidence of lung cancer and all-cause mortality in the IPF cohort was analyzed depending on pirfenidone treatment. Those who were diagnosed with lung cancer prior to IPF diagnosis were excluded.

RESULTS: Among the 5,038 patients with IPF who were eligible for the study, pirfenidone was administered to 880 patients. Median follow-up duration was 4,872.8 and 23,612.1 person-years in the groups receiving and not receiving pirfenidone, respectively. The incidence of lung cancer was significantly higher in the pirfenidone group compared to non-users [2.44 vs. 1.56 per 100 person-years; risk ratio 1.56; 95% confidence interval (CI), 1.27-1.92]. However, the risk of mortality did not differ significantly between patients receiving pirfenidone and those who did not. Further analysis was conducted to assess lung cancer development and pirfenidone therapy. Among patients with lung cancer, those treated with pirfenidone demonstrated significantly improved survival compared to those not receiving pirfenidone therapy (log-rank test, P<0.001). Pirfenidone therapy was associated with a protective effect on mortality in IPF patients with lung cancer [hazard ratio, 0.61; 95% CI, 0.43-0.85].

CONCLUSIONS: Antifibrotic therapy was associated with improved survival in patients with IPF who develop lung cancer, even though the incidence of lung cancer was higher in those receiving antifibrotic treatment compared to those do not.

PMID:39831219 | PMC:PMC11740043 | DOI:10.21037/jtd-24-1356

J Thorac Dis. 2024 Dec 31;16(12):8338-8349. doi: 10.21037/jtd-23-1908. Epub 2024 Dec 20.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has high mortality and poor prognosis, which brings enormous burdens to families and society. We conducted this meta-analysis to analyze and summarize the risk factors associated with mortality in IPF, hoping to provide reference for clinical prevention and treatment of IPF.

METHODS: We conducted a comprehensive search of PubMed, Cochrane Library, Embase, and Web of Science from inception to August 10, 2023, to include cohort studies on mortality in patients with IPF. Two researchers independently screened the studies and extracted data. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported to identify risk factors for mortality in IPF. In addition, we also carried out sensitivity analysis, Begg's and Egger's tests to evaluate the heterogeneity and publication bias.

RESULTS: Eighteen studies comprising 8,408 patients were included. The meta-analysis suggested that age (HR =1.03; 95% CI: 1.01, 1.04; P<0.001), forced vital capacity (FVC) (HR =0.97; 95% CI: 0.96, 0.99; P=0.005), FVC to predicted value ratio (FVC% pred) (HR =0.98; 95% CI: 0.97, 0.99; P<0.001), diffusing capacity of the lungs for carbon monoxide to predicted value ratio (DLCO% pred) (HR =0.98; 95% CI: 0.97, 0.99; P<0.001), gender-age-physiology (GAP) index (HR =1.70; 95% CI: 1.20, 2.40; P=0.003), and lung cancer (HR =2.75, 95% CI: 1.23, 6.15; P=0.01) were mortality-related risk factors in patients with IPF. Whereas, gender, smoking, body mass index (BMI), diffusing capacity of the lungs for carbon monoxide (DLCO), C-reactive protein (CRP), 6-minute walking distance (6MWD), pulmonary hypertension, gastroesophageal reflux, and cardiovascular disease were not statistically associated with death.

CONCLUSIONS: Age, FVC, FVC% pred, DLCO% pred, GAP index, and lung cancer have been identified as potential risk factors for mortality in patients with IPF. Due to the limited number and quality of included studies, the conclusions need to be verified by further studies.

PMID:39831203 | PMC:PMC11740034 | DOI:10.21037/jtd-23-1908

Cell Rep. 2025 Jan 18;44(2):115220. doi: 10.1016/j.celrep.2024.115220. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by excess accumulation of the extracellular matrix (ECM). The role of macrophage-fibroblast crosstalk in lung fibrogenesis is incompletely understood. Here we found that fibroblast growth factor-inducible molecule 14 (Fn14), the receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is highly induced in myofibroblasts in the lungs of IPF patients and the bleomycin-induced lung fibrosis model. TWEAK-Fn14 signaling inhibits fibroblast activation and ECM synthesis and induces chemokine expression to recruit monocytes/macrophages into the lung. Fn14 deficiency increases ECM production and impairs macrophage infiltration and differentiation, leading to exacerbated lung fibrosis and impaired alveolar regeneration in a bleomycin model. Interestingly, Fn14 deficiency diminishes an injury-induced SiglecF- CD11b- MHCIIlo intermediate macrophage (IntermM) subpopulation, which promotes alveolar type II (AT2) cell proliferation in organoid cultures. These results collectively demonstrate a protective role of TWEAK-Fn14 signaling in lung fibrosis, highlighting the complexities and multilayered regulation of macrophage-fibroblast crosstalk.

PMID:39827460 | DOI:10.1016/j.celrep.2024.115220

Eur J Med Chem. 2025 Feb 15;284:117229. doi: 10.1016/j.ejmech.2024.117229. Epub 2024 Dec 30.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound 14) was found to be the most potent in inhibiting TGF-β-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound 14 (IC50 = 0.51 ± 0.06 μM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC50 = 53.71 ± 4.78 μM). Notably, compound 14 could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-β/Smads and MAPK pathways to exert antifibrotic activity in vitro. Compound 14 significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound 14 possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound 14 promise as a potential drug candidate for the treatment of IPF.

PMID:39826937 | DOI:10.1016/j.ejmech.2024.117229

Sci Rep. 2025 Jan 17;15(1):2293. doi: 10.1038/s41598-025-85338-y.

ABSTRACT

Interstitial lung disease (ILD) has shown limited treatment advancements, with minimal exploration of circulating protein biomarkers causally linked to ILD and its subtypes beyond idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify potential drug targets and circulating protein biomarkers for ILD and its subtypes. We utilized the most recent large-scale plasma protein quantitative trait loci (pQTL) data detected from the antibody-based method and ILD and its subtypes' GWAS data from the updated FinnGen database for Mendelian randomization analysis. To enhance the reliability of causal associations, we conducted external validation and sensitivity analyses, including Bayesian colocalization and bidirectional Mendelian randomization analysis. Our study identified eight plasma proteins genetically associated with ILD or its subtypes. Among these, three proteins-CDH15 (Cadherin-15), LTBR (Lymphotoxin-beta receptor), and ADAM15 (A disintegrin and metalloproteinase 15)-emerged as priority biomarkers and potential therapeutic targets, demonstrating more reliable associations by passing a series of sensitivity analyses compared to the others. Based on these findings, we propose for the first time that CDH15, ADAM15, and LTBR hold promise as novel potential circulating protein biomarkers and therapeutic targets for the diagnosis and treatment of ILD, IPF, and sarcoidosis, respectively, especially ADAM15, and these findings have the potential to provide new perspectives for advancing the research on the heterogeneity of ILD.

PMID:39824903 | DOI:10.1038/s41598-025-85338-y