Eur Respir Rev. 2025 Jul 23;34(177):240192. doi: 10.1183/16000617.0192-2024. Print 2025 Jul.

ABSTRACT

Chronic lung diseases such as COPD, asthma, idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension are characterised by aberrant remodelling and degradation of the extracellular matrix. This is particularly evident within the basement membrane. Collagen IV, a major component of the basement membrane, is essential for maintaining structural support and regulating cell behaviour. However, disruptions in collagen IV metabolism and basement membrane integrity have been implicated in the pathogenesis of chronic lung diseases, especially in ageing populations where basement membrane turnover is compromised. Cleavage of collagen IV during basement membrane remodelling generates bioactive fragments known as matrikines, which serve as markers of tissue remodelling and potential diagnostic biomarkers. Despite the prominence of collagen IV in the basement membrane, its role in chronic lung diseases remains understudied compared to other collagen types. This review provides a comprehensive exploration of the roles of basement membrane collagen IV and its matrikines in COPD, asthma, IPF and pulmonary hypertension, emphasising their significance beyond classical matrix components. Through an analysis of clinical studies, animal models and in vitro experiments, the contributions of collagen IV to disease pathogenesis and progression are discussed. Furthermore, potential diagnostic and therapeutic implications of targeting collagen IV are outlined. By providing insights into the relationship between collagen IV and chronic lung diseases, this review aims to guide future research and clinical interventions in the field.

PMID:40701642 | DOI:10.1183/16000617.0192-2024

Sarcoidosis Vasc Diffuse Lung Dis. 2025 Jun 25;42(2):16342. doi: 10.36141/svdld.v42i2.16342.

ABSTRACT

BACKGROUND AND AIM: Progressive pulmonary fibrosis (PPF) is an umbrella term for several interstitial lung diseases characterized by the progressive proliferation of fibrous tissue within the lung interstitium. This study aimed to assess the prevalence of depressive and anxiety symptoms among PPF patients and their repercussions on quality of life.

METHODS: Thirty-seven PPF patients undergoing treatment at the Institute for Pulmonary Diseases of Vojvodina, Serbia were enrolled. The SGRQ questionnaire assessed quality of life, while the DASS-21 questionnaire evaluated anxiety and depression symptoms. Sociodemographic and clinical factors were correlated with questionnaires outcomes, and the influence of anxiety and depression symptoms on quality of life was examined.

RESULTS: Anxiety symptoms were detected in 56.75% of PPF patients and were more prevalent in patients previously diagnosed with depression and/or anxiety. Depression symptoms were detected in 45.95% of PPF patients and were more pronounced in the patients with longer duration of PPF, and positive history of malignancies. Stress symptoms were linked to lower PaO2 values and were detected in 37.84% of participants. HRQL was moderately to severely decreased and was lower in patients who, in addition to PPF, also suffered from other respiratory diseases, and was statistically significantly associated with lower DLCO values. A statistically significant correlation has been proven between the presence of anxiety, depression, and stress symptoms and HRQL, as measured through the "Symptoms" and "Impact" subscales of the SGRQ questionnaire.

CONCLUSIONS: Anxiety and depression symptoms are highly prevalent among PPF patients, exerting substantial impacts on their quality of life.

PMID:40699499 | DOI:10.36141/svdld.v42i2.16342

Sarcoidosis Vasc Diffuse Lung Dis. 2025 Jun 25;42(2):16386. doi: 10.36141/svdld.v42i2.16386.

ABSTRACT

BACKGROUND AND AIM: Homocysteine (Hcy) has been implicated in inflammatory, oxidative stress (OS), and endoplasmic reticulum (ER) stress mechanisms, which are hypothesized to contribute to the pathogenesis of interstitial lung disease (ILD). Given the paucity of evidence regarding Hcy's role in ILD, a two-sample Mendelian randomization study was performed to investigate the causal association between Hcy and ILD.

METHODS: We sourced data for total plasma Hcy from genome-wide association studies (GWAS) involving 44,147 European individuals. Data for ILD, idiopathic pulmonary fibrosis (IPF), IPF-related respiratory insufficiency, and systemic autoimmune disease-associated IPF were derived from the FinnGen consortium. To evaluate the causal association of reduced total plasma Hcy with ILD and related conditions, a range of Mendelian randomization (MR) analytical techniques were utilized to analyze the data. The results are reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). We conducted sensitivity analyses through leave-one-out procedures and Radial MR plots.

RESULTS: Our IVW estimates suggested that total plasma Hcy had a potential causal association with IPF (OR=0.649, 95%CI: 0.495-0.851), indicating that along with total plasma Hcy depressed 1 µmol/L, odds of IPF decreased 0.351. Although it seemed that decreased total plasma Hcy level is associated with lower odds of IPF-related respiratory insufficiency (OR=0.672, 95%CI: 0.489-0.924), due to the existence of horizontal pleiotropy, this causal association was not robust. In addition, MR leave-one-out and Radial MR sensitivity analyses showed there is no outlier among the selected IVs that could affect the potential causal relationship between Hcy and IPF.

CONCLUSIONS: The levels of total plasma Hcy may bear a significant association with the risk of developing IPF, a specific form of ILD. However, to definitively establish a causal relationship between elevated Hcy levels and the pathogenesis of ILD, additional well-controlled, prospective studies are indispensable.

PMID:40699496 | DOI:10.36141/svdld.v42i2.16386

Sarcoidosis Vasc Diffuse Lung Dis. 2025 Jun 25;42(2):16003. doi: 10.36141/svdld.v42i2.16003.

ABSTRACT

BACKGROUND AND AIM: To investigate the prognostic value of the HALP (Hemoglobin, Albumin, Lymphocyte, and Platelet) score for mortality in patients with Idiopathic Pulmonary Fibrosis (IPF).

METHODS: From November 2020, 39 patients with IPF were followed for a duration of 3 years. At the end of 3 years, the relationship between the initial HALP score and mortality was investigated.

RESULTS: Thirty-nine patients diagnosed with IPF were included in the study, 30 of whom were male. The average age of all patients was 68.79±7.08. At the end of the three-year follow-up period, 12 patients (33.3%) had died. When comparing patients who died and those who survived at the end of three years; significant differences were found in age, neutrophil, albumin, HALP score, FEV1%, FVC%, DLCO%, GAP score, and 6 MWD. ROC analysis for the HALP score's predictive value for mortality yielded an AUC of 0.743 and p=0.011. For a cut-off value of HALP≤30.5, p=0.01, sensitivity and specificity were 61.54% and 92.31%, respectively. Multivariate analysis for predicting mortality found HALP≤30.50 as a significant risk factor (p=0.046). An increase of one monad at the HALP cut-off (≤30.50) score level reduced the risk of death by 9.57 times. It was observed that FVC%, DLCO% and 6 MWD were not risk factors in predicting mortality. (p=0.30, p=0.08, p=0.07).

CONCLUSIONS: Our study suggests that the HALP score may serve as a negative prognostic biomarker that can be used to predict mortality in cases with IPF.

PMID:40699495 | DOI:10.36141/svdld.v42i2.16003

Mol Biol Rep. 2025 Jul 23;52(1):749. doi: 10.1007/s11033-025-10855-y.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening lung disease characterized by excessive extracellular matrix (ECM) deposition, fibroblast proliferation, and epithelial injury. Disease progression involves key signaling pathways-TGF-β, WNT/β-catenin, PI3K/AKT, and YAP/TAZ-that drive fibroblast activation, epithelial-to-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndMT), and ECM remodeling. Recent studies have highlighted the role of small extracellular vesicles (sEVs), particularly exosomes, as crucial modulators of the fibrotic microenvironment. These vesicles carry microRNAs (miRNAs), proteins, and lipids that influence fibroblast behaviour, immune signaling, and tissue architecture.Growing evidence supports the therapeutic promise of exosomes and engineered nanoparticle-exosome hybrids in targeting dysregulated fibrotic pathways and promoting tissue repair. This review examines the molecular mechanisms underlying pulmonary fibrosis, focusing on the role of exosomal crosstalk and therapeutic potential. We also incorporate emerging insights from single-cell RNA sequencing (scRNA-seq) on fibroblast heterogeneity, the influence of senescence-associated secretory phenotype (SASP) on exosomal cargo, and the limitations of current animal models in recapitulating chronic IPF. Understanding these mechanisms may facilitate the development of precision medicine approaches for managing and potentially reversing IPF progression.

PMID:40699390 | DOI:10.1007/s11033-025-10855-y

Eur J Clin Pharmacol. 2025 Jul 23. doi: 10.1007/s00228-025-03867-x. Online ahead of print.

NO ABSTRACT

PMID:40699303 | DOI:10.1007/s00228-025-03867-x

Curr Stem Cell Res Ther. 2025 Jul 22. doi: 10.2174/011574888X373765250710105821. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Stem cell-based therapy has emerged as a promising avenue for treating pulmonary degenerative disorders due to its remarkable capacity for self-renewal and differentiation into various cell types. However, concerns regarding undesired differentiation and tumorigenicity have raised questions about the safety and efficacy of cell-based therapy. The aim of the present systematic review study was to determine the therapeutic effectiveness of stem cell secretome in mitigating three pulmonary degenerative diseases, including Acute Lung Injury (ALI), Idiopathic Pulmonary Fibrosis (IPF), and Bronchopulmonary Dysplasia (BPD).

METHOD: A comprehensive search was carried out on international databases, including MEDLINE, Scopus, Web of Science, PubMed, and Embase, using related keywords according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-2020) guidelines.

RESULTS: Of 1541 retrieved studies, 136 articles were included in the present systematic review. The therapeutic effects of stem cells are primarily attributed to their paracrine secretions, specifically bioactive molecules known as the secretome, which includes exosomes and extracellular vesicles. Secretome-based therapy shows great promise in maximizing the healing potential of stem cells. However, several challenges and limitations hinder its widespread application, including scalability issues, delivery challenges, difficulty in controlling dosage, and the lack of standardized production protocols. As it is a novel therapeutic approach, its complex composition, mechanism of action, and variability in responses from the body, as well as long-term safety, remain unknown and pose challenges that necessitate further investigation and well-designed clinical trials.

CONCLUSION: The secretome exerts its protective and therapeutic effects by regulating various processes, including inflammation, oxidative stress, cell apoptosis, macrophage polarization, growth factor signaling pathways, immune cell activation, TGF-β signaling pathways, angiogenesis, structural attenuation, fibrosis resolution, pulmonary functional improvement, and alveolarization.

PMID:40698693 | DOI:10.2174/011574888X373765250710105821

Front Cell Infect Microbiol. 2025 Jul 8;15:1628481. doi: 10.3389/fcimb.2025.1628481. eCollection 2025.

ABSTRACT

The lungs are constantly exposed to airborne pathogens and depend on robust innate immune surveillance for protection. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, a core component of the innate immune system, plays a pivotal role in defending against respiratory infections caused by viruses, bacteria, and mycobacteria, including Mycobacterium tuberculosis. Dysregulation of this pathway has been linked to several chronic lung diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and asthma. Upon sensing cytoplasmic DNA, cGAS activates the STING pathway, producing type I interferons and pro-inflammatory cytokines that drive host immune response. However, many pathogens have developed strategies to evade detection or surpass cGAS-STING signaling. This systematic review highlights the molecular mechanisms governing cGAS-STING activation, its interaction with lung pathogens, and its potential as a therapeutic agent in respiratory diseases.

PMID:40697819 | PMC:PMC12279746 | DOI:10.3389/fcimb.2025.1628481

Can Respir J. 2025 Jul 15;2025:3183241. doi: 10.1155/carj/3183241. eCollection 2025.

ABSTRACT

Pulmonary fibrosis (PF) is a terminal-stage lung change in interstitial lung disease. It is characterized by proliferation of fibroblasts and deposition of a large amount of extracellular matrix, accompanied by inflammatory damage and structural destruction, caused by various reasons. The prognosis of PF is poor, and the average survival time after diagnosis is 2.5-3.5 years. The pathogenesis of PF is not yet fully understood. Its main mechanisms are diverse and include damage to alveolar epithelial cells, aggregation and activation of inflammatory cells and chemokines, proliferation of fibroblasts, transformation of myofibroblasts, production and deposition of large amounts of collagen, autophagy, epithelial-mesenchymal transition (EMT), mitochondrial quality-control disorders, microRNA, and circular RNA. The diagnosis of PF is mainly based on the comprehensive evaluation of clinical manifestations, imaging characteristics, and histopathological examination. Medical and family history to determine all potential causes of PF. For PF of unknown etiology, one can refer to the Official Clinical Practice Guideline of idiopathic pulmonary fibrosis (IPF) for definitive diagnosis. In terms of treatment, modern medications such as pirfenidone and nintedanib can inhibit the progression of PF to some extent and improve lung function. However, there is no drug that can significantly improve PF, except for lung transplantation. In addition, many patients are forced to stop taking medication due to adverse reactions in clinical practice. Therefore, to better control the progression of disease, some new drugs have been developed based on the pathogenesis of PF. However, there is still controversy over their efficacy and widespread clinical application in PF, and the evidence is limited. The results of in vitro and in vivo experiments, as well as randomized clinical trials, indicate that traditional Chinese medicine (TCM) can improve PF by intervening in multiple pathways and targets. This study combines the pathogenesis and diagnosis of PF, focusing on the intervention mechanism and targets of TCM in the treatment of PF, so as to provide more options for clinical treatment and provide scientific basis for a new approach to better management of PF.

PMID:40697404 | PMC:PMC12283196 | DOI:10.1155/carj/3183241

Biomed Pharmacother. 2025 Jul 21;190:118370. doi: 10.1016/j.biopha.2025.118370. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal condition associated with excessive interstitial collagen accumulation and irreversible lung function decline, for which there is no effective cure. Hence, this study evaluated the dose-dependent anti-fibrotic effects of bone marrow mesenchymal stem cell-derived extracellular vesicles (BM-MSC-EVs) in transforming growth factor (TGF)-β1-stimulated human dermal myofibroblasts (1 ×107-1 ×1010 BM-MSC-EVs) and TGF-β1-stimulated lung myofibroblasts isolated from non-IPF versus and IPF patients (1 ×106-1 ×108 BM-MSC-EVs) after 72 h in culture; and when intranasally-administered therapeutically (from days 21-28 post-injury) to bleomycin (BLM)-injured mice (2.5 ×108-2.5 ×1010 BM-MSC-EVs). In each case, changes in myofibroblast differentiation, collagen I deposition, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 levels, and MMP-2:TIMP-2 and MMP-9:TIMP-1 ratios were assessed. BM-MSC-EVs significantly attenuated human dermal and non-IPF patient-derived lung myofibroblast differentiation and collagen I deposition in an inverse dose-dependent manner after 72 h, with the lowest doses evaluated inducing the strongest inhibitory effects. Similarly, BM-MSC-EVs therapeutically reduced the BLM-induced lung TGF-β1 expression and signal transduction, myofibroblast differentiation and collagen I deposition, and restored the BLM-induced loss of dynamic lung compliance in an inverse dose-dependent manner in vivo, after 7-days of treatment. BM-MSC-EVs promoted the MMP-2:TIMP-2 ratio in human dermal myofibroblasts or the MMP-9:TIMP-1 ratio in human lung myofibroblasts and the murine lung as part of their anti-fibrotic effects. Notably, BM-MSC-EVs failed to exert any anti-fibrotic effects in TGF-β1-stimulated lung myofibroblasts isolated from IPF patients. These findings suggested that BM-MSC-EVs may provide an anti-fibrotic treatment option for early-to-moderate IPF, but may not be effective against advanced IPF.

PMID:40695046 | DOI:10.1016/j.biopha.2025.118370

ERJ Open Res. 2025 Jul 21;11(4):01142-2024. doi: 10.1183/23120541.01142-2024. eCollection 2025 Jul.

ABSTRACT

INTRODUCTION: The pathophysiology of respiratory complications in post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) is poorly understood, but a high incidence of progressive pulmonary fibrosis was anticipated. Deupirfenidone (LYT-100) is a selectively deuterated form of pirfenidone that retains antifibrotic and anti-inflammatory activity but with improved tolerability. This study evaluated the safety and efficacy of deupirfenidone in PASC patients with respiratory complications.

METHODS: Global, double-blind, randomised placebo-controlled trial evaluating 750 mg deupirfenidone twice daily versus placebo for 3 months in PASC patients with respiratory complications following hospitalisation for acute COVID-19 infection severe enough to necessitate supplemental oxygen (NCT04652518).

RESULTS: 185 patients were randomised and treated (95 with deupirfenidone, 90 with placebo), with 177 included in the modified intention-to-treat population. The mean age was 54.5 years, 62.7% were male and 10.7% had prior mechanical ventilation. The 6-min walk distance improved across both arms between baseline and day 91 (deupirfenidone 44.3 m (95% CI 24.8-63.8 m) versus placebo 48.8 m (95% CI 29.2-68.4 m); p=0.70). The most common treatment-emergent adverse events (TEAEs) for deupirfenidone versus placebo were nausea (9.5% versus 1.1%), upper abdominal discomfort (5.3% versus 2.2%) and dyspepsia (6.3% versus 1.1%). TEAEs leading to trial drug discontinuation were 11.6% for deupirfenidone and 4.4% for placebo. The proportion of discontinuations considered at least possibly related to treatment was 8.6% for deupirfenidone and 2.4% for placebo.

DISCUSSION: Most patients with PASC and respiratory complications showed significant improvement over 91 days irrespective of treatment assignment. Deupirfenidone was well tolerated, with low rates of TEAEs, which supports further investigation in patients with idiopathic pulmonary fibrosis.

PMID:40692836 | PMC:PMC12278312 | DOI:10.1183/23120541.01142-2024

Am J Physiol Cell Physiol. 2025 Jul 21. doi: 10.1152/ajpcell.00604.2024. Online ahead of print.

ABSTRACT

Small animal models are crucial for investigating idiopathic pulmonary fibrosis (IPF) and developing preclinical therapeutic strategies. However, there are several limitations to the quantitative measurements used in the longitudinal assessment of experimental lung fibrosis, e.g., histological or biochemical analyses introduce inter-individual variability, while image-derived biomarker has yet to directly and accurately quantify the severity of lung fibrosis. This study investigates artificial intelligence (AI)-assisted, end-to-end, semi-quantitative measurement of lung fibrosis using in vivo micro-CT. Based on the bleomycin (BLM)-induced lung fibrosis mouse model, the AI model predicts histopathological scores from in vivo micro-CT images, directly correlating these images with the severity of lung fibrosis in mice. Fibrosis severity was graded by the Ashcroft scale: none (0), mild (1-3), moderate (4-5), severe (≥6).The overall accuracy, precision, recall, and F1 scores of the lung fibrosis severity-stratified 3-fold cross validation on 225 micro-CT images for the proposed AI model were 92.9%, 90.9%, 91.6%, and 91.0%. The overall area under the receiver operating characteristic curve (AUROC) was 0.990 (95% CI: 0.977, 1.000), with AUROC values of 1.000 for none (100 images, 95% CI: 0.997, 1.000), 0.969 for mild (43 images, 95% CI: 0.918, 1.000), 0.992 for moderate (36 images, 95% CI: 0.962, 1.000), and 0.992 for severe (46 images, 95% CI: 0.967, 1.000). Preliminary results indicate that AI-assisted, in vivo micro-CT-based semi-quantitative measurements of murine are feasible and likely accurate. This novel method holds promise as a tool to improve the reproducibility of experimental studies in animal models of IPF.

PMID:40691039 | DOI:10.1152/ajpcell.00604.2024

JMIR Res Protoc. 2025 Jul 21;14:e73219. doi: 10.2196/73219.

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that affects approximately 0.5% to 1% of the population in the United States and Northern Europe. Interstitial lung disease (ILD) is the most common and severe pulmonary manifestation of RA, collectively referred to as RA-associated ILD (RA-ILD). RA-ILD contributes significantly to morbidity and mortality and often presents with a variable clinical course. Although corticosteroids and disease-modifying antirheumatic drugs (DMARDs) remain the cornerstone of RA management, their role in RA-ILD is less clearly defined. In contrast, antifibrotic therapies such as pirfenidone and nintedanib, initially developed for idiopathic pulmonary fibrosis, are now being explored for their potential in treating fibrosing variants of RA-ILD. Despite increasing clinical use, no systematic review has comprehensively compared the safety and efficacy of antifibrotic versus anti-inflammatory therapies in chronic RA-ILD.

OBJECTIVE: This study aims to compare the impact of antifibrotic and anti-inflammatory therapies on lung function, radiologic progression, clinical outcomes, and safety in patients with chronic RA-ILD.

METHODS: This study will follow PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and is registered with PROSPERO (CRD42024583847). A comprehensive search of PubMed, Embase, and the Cochrane Library will be conducted for studies published between January 1991 and August 2024. Eligible studies will include adult patients (aged ≥18 years) with a diagnosis of RA and confirmed ILD based on radiological or histopathological findings who have been treated with either antifibrotic or anti-inflammatory therapies. The PECOS (Population, Exposure, Comparator, Outcome, Study Design) framework will be used to define inclusion criteria. The primary outcomes assessed in this review will include the following pulmonary function parameters: forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide. Anti-inflammatory therapies will be stratified into corticosteroids, conventional synthetic DMARDs, and biologic DMARDs to account for heterogeneity. The Cochrane Risk of Bias 2 (RoB 2) and Risk of Bias in Non-randomized Studies - of Interventions (ROBINS-I) tools will be used for quality assessment, and GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology will be used to evaluate the certainty of evidence.

RESULTS: The literature search and screening commenced in August 2024, and data extraction is underway. The final results are expected by December 2025.

CONCLUSIONS: This systematic review and meta-analysis will provide a comprehensive comparison of antifibrotic and anti-inflammatory therapies in the treatment of chronic RA-ILD. The findings will help inform clinical decision-making, support evidence-based treatment selection, and identify gaps in current research. By addressing both efficacy and safety, this review aims to guide future studies and improve patient outcomes for this complex and debilitating condition.

TRIAL REGISTRATION: PROSPERO CRD42024583847; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024583847.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/73219.

PMID:40690765 | DOI:10.2196/73219

Tissue Eng Part C Methods. 2025 Jul;31(7):248-260. doi: 10.1177/19373341251360742.

ABSTRACT

Fibrosis causes altered tissue structure and function in multiple organs due to a complex interplay between inflammatory cells, myofibroblasts, and extracellular matrix (ECM) components. While it is known that T cells play a role in tissue fibrosis, it remains unclear how they modulate cellular interactions to activate fibrogenesis. Since conventional monolayer cell cultures do not mimic the tissue complexity and cellular heterogeneity in the fibrotic tissue environment, there is a need to bridge the gap between monolayer cultures and in vivo animal studies of fibrosis by providing a more predictive 3D model for preclinical drug screening and mechanistic studies of fibrotic diseases. We have developed 3D skin-like tissues harboring blood-derived human T cells that offer a model to better understand the role these cells play in the pathogenesis of tissue fibrosis. In the current study, we constructed skin-like tissues harboring T cells, fibroblasts, macrophages, and keratinocytes and analyzed them using tissue analysis and single-cell RNA sequencing (scRNA-seq). Skin-like tissues constructed with fully autologous cells (donor-matched fibroblasts and T cells) or nonautologous cells (mismatched fibroblasts and T cells) derived from patients with scleroderma (SSc) demonstrated normal distribution of tissue markers of epithelial differentiation and proliferation. T cells in these tissues were viable and functional as seen by elevated IL-6 production by enzyme-linked immunosorbent assay, expression of alpha smooth muscle actin in fibroblasts, and scRNA-seq. We used scRNA-seq to identify five distinct T cell subpopulations: CD8 T cells (identified by KLRK1 and CD8A), proliferating CD4 T cells (identified by PCNA, MKI67, and CD4), activated CD4 T cells (identified by IL2RA, RORA, and CD4), naïve CD4 T cells (identified by CCR7 and CD4), and Th17 CD4 T cells (identified by KLRB1, RORA, IL2RA, and CD4). Fabrication of complex 3D tissues are an important step toward establishing tissue engineering approaches to study fibrosis in multiple diseases, including SSc, idiopathic pulmonary fibrosis, as well as liver and kidney fibrosis. Understanding the roles of T cells in the ECM environment and their interactions with fibroblasts will support the development of novel treatments to reverse fibrosis and restore normal tissue and organ function.

PMID:40690724 | DOI:10.1177/19373341251360742

J Thorac Dis. 2025 Jun 30;17(6):3962-3970. doi: 10.21037/jtd-2024-2160. Epub 2025 Jun 23.

ABSTRACT

BACKGROUND: Interstitial lung disease (ILD) is a heterogeneous condition that requires diagnosis and treatment through an integrated approach that combines the clinical background and radiological and histopathological findings. Transbronchial lung cryobiopsy (TBLC) has the advantage of obtaining larger tissue samples with minimal tissue damage compared to transbronchial lung biopsy, and represents a safer alternative to surgical lung biopsy. Recently, 1.7-mm single-use cryoprobes have been widely used, however, the safety and usefulness of TBLC with these probes remain unclear. The aim of this study was to evaluate the procedural details, safety, and changes in diagnostic confidence with multidisciplinary discussion (MDD) following TBLC.

METHODS: We conducted a retrospective study of TBLC cases at a single university hospital in Japan. Between August 2023 to June 2024, 25 patients were enrolled in this study. Biopsies were obtained using a 1.7-mm single-use probe with a freezing duration of 5 s; the mean sample area was 16.0 mm2, and the mean maximum diameter was 5.47 mm.

RESULTS: Complications included moderate hemorrhage in three patients (12%) and mild pneumothorax in one patient (4%). No acute exacerbations of ILD were observed. Diagnostic confidence improved after MDD in 5 out of 6 cases (83.3%) of idiopathic pulmonary fibrosis (IPF) and 7 out of 8 cases (87.5%) of hypersensitivity pneumonitis (HP).

CONCLUSIONS: The incorporation of TBLC pathological findings in the MDD improved diagnostic certainty and facilitated decisions regarding treatment strategies. TBLC using a 1.7-mm single-use probe with a freezing duration of 5 s can safely obtain sufficient tissue specimens for the diagnosis of ILD.

PMID:40688314 | PMC:PMC12268596 | DOI:10.21037/jtd-2024-2160

JHLT Open. 2025 May 29;9:100296. doi: 10.1016/j.jhlto.2025.100296. eCollection 2025 Aug.

ABSTRACT

Some patients with pulmonary fibrosis (PF) can have severe and fixed chest wall retraction; others regain the shape of their original rib cage once the lungs are removed. These 2 possibilities determine the size of the lung graft to be allocated but are not predictable with classical respiratory tests or computed tomography (CT) scan. We first measured chest wall elastance (Ecw) with esophageal pressure on the day of transplantation (group 1) and then during pretransplant medical check-up, and used for donor selection (group 2). Twenty patients in group 1 had low pretransplantation actual total lung capacity/predicted total lung capacity (pTLC) ratio that was not correlated with Ecw. The amount of transplanted lung TLCtransplanted/pTLC was correlated to Ecw (R2 = 0.43, p = 0.003). Patient with higher Ecw required lung resection and had more primary graft dysfunction. In group 2, 20 patients' Ecw measurements allowed for increase in TLCtransplanted/pTLC from 79 ± 20% to 93 ± 18%, p = 0.023 with only 2 lung resections. Ecw can be measured before transplantation to optimize size mismatch and lung resection.

PMID:40687314 | PMC:PMC12273421 | DOI:10.1016/j.jhlto.2025.100296

Turk J Med Sci. 2025 Mar 24;55(3):644-651. doi: 10.55730/1300-0144.6011. eCollection 2025.

ABSTRACT

BACKGROUND/AIM: Systemic sclerosis (SSc) is a complex autoimmune disease marked by vascular abnormalities and fibrosis. This study aimed to compare pulmonary artery wall thickness (PAWT) among SSc patients without PAH, patients with idiopathic PAH (IPAH), and healthy controls, and to explore the clinical implications of increased PAWT in SSc patients.

MATERIALS AND METHODS: This cross-sectional study included 60 SSc patients, 30 patients with IPAH, and 40 age- and sex-matched healthy controls. All participants underwent transthoracic echocardiographic assessment. In SSc patients, modified Rodnan skin score (mRSS), demographic characteristics, disease duration, type of skin and lung involvement, and autoantibody status were analyzed.

RESULTS: PAWT was significantly higher in the SSc group than in the control group. There was a strong correlation between PAWT and mRSS, with mRSS identified as an independent risk factor for increased PAWT. Additionally, a correlation was found between PAWT and echocardiographic parameters, particularly systolic pulmonary artery pressure (sPAP).

CONCLUSION: PAWT is elevated in SSc patients compared to healthy controls. This may be associated with underlying vascular and fibrotic changes in SSc. Furthermore, the strong correlation between PAWT and echocardiographic markers of PAH suggests that PAWT could serve as a predictive marker for future PAH. In addition, the strong correlation between increased PAWT and mRSS suggests that elevated PAWT may represent a vascular component of SSc. Future longitudinal studies are needed to clarify the clinical significance of PAWT in SSc and to define its potential role in disease management.

PMID:40686711 | PMC:PMC12270313 | DOI:10.55730/1300-0144.6011

Zhongguo Zhong Yao Za Zhi. 2025 May;50(10):2825-2840. doi: 10.19540/j.cnki.cjcmm.20250208.201.

ABSTRACT

This study aims to explore the pharmacodynamic material basis of Jinbei Oral Liquid(JBOL) against idiopathic pulmonary fibrosis(IPF) based on serum pharmacochemistry and network pharmacology. The ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS/MS) technology was employed to analyze and identify the components absorbed into rat blood after oral administration of JBOL. Combined with network pharmacology, the study explored the pharmacodynamic material basis and potential mechanism of JBOL against IPF through protein-protein interaction(PPI) network construction, "component-target-pathway" analysis, Gene Ontology(GO) functional enrichment, and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. First, a total of 114 compounds were rapidly identified in JBOL extract according to the exact relative molecular mass, fragment ions, and other information of the compounds with the use of reference substances and a self-built compound database. Second, on this basis, 70 prototype components in blood were recognized by comparing blank serum with drug-containing serum samples, including 28 flavonoids, 25 organic acids, 4 saponins, 4 alkaloids, and 9 others. Finally, using these components absorbed into blood as candidates, the study obtained 212 potential targets of JBOL against IPF. The anti-IPF mechanism might involve the action of active ingredients such as glycyrrhetinic acid, cryptotanshinone, salvianolic acid B, and forsythoside A on core targets like AKT1, TNF, and ALB and thereby the regulation of multiple signaling pathways including PI3K/AKT, HIF-1, and TNF. In conclusion, JBOL exerts the anti-IPF effect through multiple components, targets, and pathways. The results would provide a reference for further study on pharmacodynamic material basis and pharmacological mechanism of JBOL.

PMID:40686151 | DOI:10.19540/j.cnki.cjcmm.20250208.201

Aging Cell. 2025 Jul 20:e70174. doi: 10.1111/acel.70174. Online ahead of print.

ABSTRACT

Smoking is one of the most recognized risk factors for pulmonary fibrosis (PF). However, the underlying mechanism is not well understood. This study reveals smoking increases the risk of developing idiopathic PF (IPF) and that smoked IPF patients exhibit higher levels of senescence markers than non-smoker IPF patients. Moreover, smoking enhances bleomycin (Bleo)-induced PF, along with obvious senescence of type II alveolar (AT2) cells. RNA-seq assay identifies cigarette downregulates protection of telomeres 1 (POT1), which is then validated to decrease in smoked PF patients and mice via upregulating the methyltransferase MECP2. Mechanistically, MECP2 binds to the DNA methyltransferases (DNMTs)-induced methylated CpG island in the POT1 promoter, and smoking inhibits the transcriptional activity of the CpG island. The transcription factor FOXP2 could bind to this CpG island to promote POT1 transcription. However, this process is inhibited by forming a MECP2-FOXP2 complex, which blunts the FOXP2-POT1 DNA binding. siRNA-mediated POT1 knockdown promoted AT2 cell senescence in a p-ATM and p-ATR-dependent manner and secreted inflammatory and profibrotic factors, further promoting fibrotic response in fibroblasts. In vivo, delivery of the adeno-associated virus 9-POT1 (AAV9-POT1) vector inhibits cigarette-induced cell senescence and effectively alleviates PF in mice. These findings demonstrate that POT1 is an essential protector in PF by protecting against AT2 cell senescence.

PMID:40685333 | DOI:10.1111/acel.70174

Lancet Respir Med. 2025 Jul 14:S2213-2600(25)00129-8. doi: 10.1016/S2213-2600(25)00129-8. Online ahead of print.

ABSTRACT

The global incidence and prevalence of interstitial lung disease (ILD) are difficult to determine due to the rarity of the condition, inconsistent case ascertainment and reporting methods, and differences in risk factors, burden of exposures, and access to health-care systems across geographical areas. With these caveats, several studies have reported an increased incidence and prevalence of ILD over time. Idiopathic pulmonary fibrosis is the most common and extensively studied ILD, whereas connective tissue disease-associated ILD and hypersensitivity pneumonitis display the most geographical variability. Except for idiopathic pulmonary fibrosis, connective tissue disease-associated ILD, hypersensitivity pneumonitis, and sarcoidosis, few data are available for other ILDs. Access to health care remains uneven particularly in low-income and middle-income countries, leading to major health disparities. Socioeconomic inequalities also affect morbidity and mortality within and across countries. We performed a non-systematic review of the most recent literature on the epidemiology and burden of ILD, and highlighted areas where substantial gaps in knowledge remain and further studies are needed. The introduction of new tools, including nationwide health-care databases and monitoring of air pollution exposure, is opening new avenues for ILD epidemiology research; however, we are only at the beginning of understanding how the interaction between genetic and environmental factors contributes to the rising burden of these deadly diseases.

PMID:40684782 | DOI:10.1016/S2213-2600(25)00129-8