Nat Commun. 2025 Aug 4;16(1):7150. doi: 10.1038/s41467-025-61880-1.

ABSTRACT

Healthy alveolar repair relies on the ability of alveolar stem cells to differentiate into specialized epithelial cells for gas exchange. In chronic fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF), this regenerative process is abnormal but the underlying mechanisms remain unclear. Here, using human lung tissue that represents different stages of disease and a 33-plex single-cell imaging mass cytometry (IMC), we present a high-resolution, temporo-spatial cell atlas of the regenerating alveolar niche. With unbiased mathematical methods which quantify statistically enriched interactions, CD206himacrophage subtype and an alveolar basal intermediate epithelial cell emerge as the most statistically robust spatial association in the epithelial and immune cell interactome, found across all stages of disease. Spatially resolved receptor-ligand analysis further offers an in silico mechanism by which these macrophages may influence epithelial regeneration. These findings provide a foundational step toward understanding immune-epithelial dynamics in aberrant alveolar regeneration in IPF.

PMID:40759629 | DOI:10.1038/s41467-025-61880-1

Cureus. 2025 Jul 4;17(7):e87264. doi: 10.7759/cureus.87264. eCollection 2025 Jul.

ABSTRACT

Hypereosinophilic syndrome (HES) is a rare condition characterized by persistent eosinophilia (eosinophil count ≥1.5 × 109/L) and end-organ damage in the absence of an identifiable cause. Cardiac involvement is common and may lead to life-threatening complications. Cystic fibrosis (CF) is a chronic multisystem disease predominantly associated with neutrophilic inflammation, and eosinophilic disorders are less often reported in this population. A 32-year-old woman with CF, complicated by CF-related diabetes and pancreatic insufficiency, presented with chest pain and peripheral eosinophilia (3.2 × 10⁹/L); infectious, autoimmune, and allergic evaluations were negative. Imaging revealed perimyocarditis, and systemic corticosteroids were initially effective but discontinued due to cushingoid side effects and anasarca. She subsequently experienced a recurrence of chest pain accompanied by eosinophilia (1.7 × 10⁹/L), and a diagnosis of idiopathic HES was made based on persistent eosinophilia, cardiac involvement, and exclusion of secondary causes. She responded favorably to monthly subcutaneous mepolizumab, a monoclonal antibody that prevents interleukin-5 (IL-5) from binding to its receptor, thereby inhibiting the recruitment and activation of eosinophils, with resolution of eosinophilia and improvement in symptoms. This case underscores the importance of considering HES in CF patients presenting with unexplained eosinophilia and extrapulmonary symptoms. It also illustrates the efficacy of targeted biologic therapy in managing idiopathic HES when corticosteroids are poorly tolerated.

PMID:40755600 | PMC:PMC12318349 | DOI:10.7759/cureus.87264

Expert Rev Clin Immunol. 2025 Aug 3. doi: 10.1080/1744666X.2025.2543473. Online ahead of print.

ABSTRACT

INTRODUCTION: This network meta-analysis (NMA) of randomized controlled trials (RCTs) aimed to evaluate the efficacy and safety of pharmacotherapies for progressive fibrotic-interstitial lung diseases (PF-ILDs) to identify optimal treatments.

METHODS: We searched for RCTs on PF-ILD [idiopathic pulmonary fibrosis (IPF), connective tissue disease-ILD (CTD-ILD), chronic hypersensitivity pneumonitis (CHP), and pulmonary sarcoidosis] pharmacotherapies until 5 June 2025. NMA assessed efficacy [forced vital capacity, diffusing capacity of lungs for carbon monoxide, 6-minute-walk distance] and safety [serious adverse events (SAEs) and all-cause mortality] (PROSPERO: CRD42024554475).

RESULTS: We included sixty-five studies (13,521 participants) for forty-eight drugs in IPF, ten studies (1,508 participants) for eight drugs in CTD-ILD, four studies (259 participants) for three drugs in CHP, and nine studies (525 participants) for nine drugs in pulmonary sarcoidosis. In IPF, pirfenidone, nintedanib, and IFNγ-1b slowed lung function decline and reduced mortality. In CTD-ILD, pirfenidone, nintedanib, tocilizumab, and cyclophosphamide improved lung function and reduced mortality, with higher SAEs for nintedanib and cyclophosphamide. Pirfenidone and prednisolone benefited CHP, while budesonide improved lung function in pulmonary sarcoidosis.

CONCLUSIONS: Anti-fibrotic drugs - Pirfenidone and nintedanib effectively slow disease progression and reduce mortality in PF-ILDs. Emerging therapies like IFNγ-1b warrant further research, underscoring the need for large, high-quality RCTs.

PMID:40754799 | DOI:10.1080/1744666X.2025.2543473

Respir Investig. 2025 Aug 2;63(5):983-990. doi: 10.1016/j.resinv.2025.07.018. Online ahead of print.

ABSTRACT

BACKGROUND: Unilateral upper lung field pulmonary fibrosis (upper-PF) that is radiologically consistent with pleuroparenchymal fibroelastosis occasionally develops after lung cancer surgery in the operated side. However, the incidence and perioperative risk factors for unilateral upper-PF development remain unclear in lung cancer patients with interstitial lung disease (ILD).

METHODS: All consecutive lung cancer patients with ILD who underwent complete resection from 2008 to 2020 were investigated retrospectively. Pre-/postoperative characteristics were compared between patients with and without unilateral upper-PF. Cumulative incidence curves were estimated using competing risk analysis.

RESULTS: Among the 110 included patients, 20 patients (18.2 %) were diagnosed as developing unilateral upper-PF. The median interval from lung cancer surgery to unilateral upper-PF diagnosis was 16.5 months. The 3-, 5- and 10-year cumulative incidence was 15.5 %, 16.7 % and 20.1 %. In multivariable analysis, the presence of pulmonary apical cap and idiopathic pulmonary fibrosis (IPF) were independent perioperative risk factors. The 3-year cumulative incidence of unilateral upper-PF was 38.7 % in patients with pulmonary apical cap and 37.5 % in IPF patients. Pleural effusion at 6 months postoperatively was more frequent in patients who developed unilateral upper-PF later. During the clinical courses of 20 patients with unilateral upper-PF, 19 patients suffered from subsequent respiratory symptoms related to upper-PF and 14 patients died. Overall survival after unilateral upper-PF diagnosis was poor with a median of 33 months.

CONCLUSIONS: Thoracic surgeons and pulmonologists should recognize that unilateral upper-PF sometimes develops mostly within 3 years after lung cancer surgery as a poor prognostic late complication in ILD patients.

PMID:40753729 | DOI:10.1016/j.resinv.2025.07.018

Cell Biosci. 2025 Aug 2;15(1):114. doi: 10.1186/s13578-025-01442-6.

ABSTRACT

The integrity and stability of DNA, an essential genetic material, need to be maintained for normal cellular function, growth, and development. The DNA damage response (DDR) constitutes a complex, sophisticated, and extensive signaling network that preserves genomic stability under stress. It can be divided into the DNA damage surveillance system and DNA damage repair system, which work in concert to ensure genomic integrity. When DNA damage surpasses the repair capacity of the DDR, unrepaired DNA damage accumulates, inducing cellular senescence and altering the fate of alveolar epithelial cells; this process is intricately linked to the onset, progression, and management of developmental and chronic lung diseases. In this review, recent research on the pathogenic mechanisms of DDR in respiratory diseases across the lifespan, including bronchopulmonary dysplasia, bronchial asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis, as well as progress in the development of associated targeted therapeutic strategies, is synthesized.

PMID:40753255 | DOI:10.1186/s13578-025-01442-6

Nat Commun. 2025 Aug 2;16(1):7099. doi: 10.1038/s41467-025-61795-x.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo. We thus identify YAP-TEAD/LOX inhibition in alveolar type II cells as a promising potential therapy for IPF patients.

PMID:40753090 | DOI:10.1038/s41467-025-61795-x

Acad Radiol. 2025 Aug 1:S1076-6332(25)00704-4. doi: 10.1016/j.acra.2025.07.034. Online ahead of print.

ABSTRACT

Radiolabeled fibroblast activation protein inhibitors (FAPIs) have emerged as promising tracers for molecular imaging, particularly in the field of oncology. However, their potential extends beyond cancer applications to a wide range of non-oncological conditions characterized by fibrosis, inflammation, and tissue remodeling. This review addresses the expanding role of FAPI-based imaging in non-malignant diseases, related to its ability to visualize and quantify fibroblast activation, a key process in various pathological conditions. We discuss the mechanism of action of FAPIs, their radiolabeling techniques, and their pharmacokinetics and biodistribution. The review then delves into the evidence supporting the use of FAPI-PET and SPECT in specific non-oncological applications, including cardiovascular diseases (myocardial infarction, atherosclerosis, cardiomyopathies, cardiac amyloidosis, and systemic vasculitis), liver fibrosis, pulmonary fibrosis (idiopathic pulmonary fibrosis and other interstitial lung diseases), renal diseases (chronic kidney disease, lupus nephritis, and IgA nephropathy), bone and joint diseases (rheumatoid arthritis, psoriatic arthritis, periprosthetic joint infection, and other bone and joint pathologies), and other inflammatory conditions (Crohn's disease and IgG4-related disease). We analyze the diagnostic performance of FAPI imaging in these conditions, comparing it with conventional imaging techniques and highlighting its advantages and limitations. Finally, we discuss the challenges and future directions in the field, including the need for standardization, validation studies, and the development of quantitative imaging biomarkers to improve the clinical utility of FAPI-based imaging in non-oncological applications. The aim of this review is to provide a comprehensive overview of the current state of FAPI imaging in non-oncological diseases, highlighting its potential to improve diagnosis, treatment planning, and monitoring of these conditions.

PMID:40753024 | DOI:10.1016/j.acra.2025.07.034

Acta Biomater. 2025 Jul 31:S1742-7061(25)00577-X. doi: 10.1016/j.actbio.2025.07.068. Online ahead of print.

ABSTRACT

Inhalable nucleic acid drug delivery systems have garnered increasing attention as a promising strategy for the treatment of chronic pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF). These diseases are often characterized by chronic inflammation, airway remodeling, and progressive lung dysfunction, posing significant clinical challenges. Nucleic acid therapeutics, including plasmid DNA, messenger RNA (mRNA), microRNA (miRNA), small interfering RNAs (siRNAs), and antisense oligonucleotides (ASOs), offer the potential to correct genetic defects, modulate aberrant gene expression, or suppress pathogenic signaling pathways. The inhalation route enables direct, non-invasive access to the lungs, offering localized delivery, rapid onset of action, and reduced systemic side effects. However, the lung presents multiple biological barriers that limit the delivery and activity of nucleic acids, including mucus clearance, enzymatic degradation, alveolar macrophage uptake, and cellular membrane penetration. To address these challenges, various delivery vectors-ranging from viral vectors to non-viral systems such as lipid nanoparticles, polymeric carriers, and hybrid nanomaterials-have been engineered to enhance stability, targeting, and transfection efficiency. This review highlights recent advances in inhalable nucleic acid delivery platforms, discusses the critical physiological and pathological barriers in the pulmonary microenvironment, and outlines current clinical progress. Finally, we explore future directions and challenges toward clinical translation of these innovative therapies. STATEMENT OF SIGNIFICANCE: Chronic pulmonary diseases, including COPD, asthma, IPF, and CF, remain among the leading causes of morbidity and mortality worldwide, with limited treatment options that target disease pathogenesis at the molecular level. Nucleic acid therapeutics offer transformative potential to precisely regulate gene expression, correct mutations, and modulate inflammatory or fibrotic pathways. However, effective delivery to the lungs remains a critical barrier to clinical translation. This review highlights the emerging field of inhalable nucleic acid delivery systems, integrating recent advances in nanocarrier design, pulmonary targeting strategies, and the navigation of biological barriers. By bridging nucleic acid pharmacology with pulmonary drug delivery science, this review provides a comprehensive framework for the rational design and clinical development of next-generation genetic therapies for respiratory diseases. It also offers forward-looking perspectives on overcoming current translational hurdles, thereby accelerating the realization of precision gene therapy for chronic lung disorders.

PMID:40752856 | DOI:10.1016/j.actbio.2025.07.068

BMC Pulm Med. 2025 Aug 1;25(1):368. doi: 10.1186/s12890-025-03865-w.

ABSTRACT

INTRODUCTION: Telomere and telomerase abnormalities play critical roles in interstitial lung diseases (ILDs). This study aimed to explore the telomere lengths (TL) in cells in the peripheral blood and bronchoalveolar lavage fluid (BALF) of healthy individuals and patient with various types of non-idiopathic pulmonary fibrosis (IPF)-ILD and to evaluate the correlation between TL and clinical indicators.

METHODS: We enrolled 48 patients with ILDs and 21 control individuals who presented at our hospital from September 2023 to September 2024. The relative TL of genomic deoxyribonucleic acid (DNA) in peripheral blood mononuclear cells (PBMCs) and BALF macrophages were measured using quantitative polymerase chain reaction (qPCR).

RESULTS: Patients with non-IPF-FILD had significantly shorter PBMC TL than controls (p < 0.001) and non-F-ILD patients (p < 0.001). There was a linear correlation between the TL in cells in the BALF and peripheral blood. Compared with control individuals, patients with non-F-ILD also had no significant difference in TL in cells both in the PBMC and BALF. TL was strongly associated with the presence of autoantibodies (η2 = 0.275, p = 0.012) and the use of immunosuppressants (η2 = 0.246, p = 0.010).

CONCLUSIONS: The PBMC TL of non-IPF-FILD patients were significantly shorter than that of control and non-F-ILD patients. However, there was no significant difference in TL in cells in the BALF and peripheral blood between non-F-ILD patients and control individuals. TL were closely correlated with the presence of autoantibodies and treatment with immunosuppressants.

PMID:40751243 | DOI:10.1186/s12890-025-03865-w

Sci Rep. 2025 Aug 1;15(1):28071. doi: 10.1038/s41598-025-13584-1.

ABSTRACT

Melanoma is still one of the most aggressive cancers, with global incidence and mortality rates expected to rise significantly by 2040. Surgical excision with adequate safety margins remains the standard treatment for primary cutaneous melanoma. However, the therapeutic approach to treat advanced stages or disease recurrence in melanoma is still challenging. Although initial responses to combined targeted therapies and immune checkpoint inhibitors often achieve clinical success, disease progression remains difficult to manage. Thus, there is an urgent need for novel and unexplored therapeutic strategies. Pirfenidone (PFD) is an antifibrotic drug approved for Idiopathic Pulmonary Fibrosis, with anti-inflammatory, and anti-oxidant properties. Its primary mechanism involves Transforming Growth Factorβ signalling downregulation, alongside with the suppression of cytokine and reactive oxygen species (ROS) release. Recently, it has been suggested that PFD may function as furin convertase enzyme inhibitor. Furin is involved in many physiological and pathological processes such as BRAF oncogene activation. In this study, we investigated the mechanisms of antitumoral effect of PFD in BRAF mutated human melanoma cell lines. Docking analysis revealed a close interaction between PFD and furin convertase active site. In vitro studies revealed that PFD reduced cell proliferation, clonogenicity, and invasiveness. Interestingly, the early antioxidant effect observed during PFD treatment was later replaced by a marked increase in ROS levels, along with p21 upregulation and induction of apoptosis. This multi-angle approach highlights a key role of furin in melanoma cell aggressiveness. Although, the present study lacks clinical data from melanoma patients, our observations suggest that PFD may represent a treatment option for metastatic melanoma cases that are resistant to conventional therapeutic interventions, through a drug repurposing approach.

PMID:40751072 | DOI:10.1038/s41598-025-13584-1

Int Immunopharmacol. 2025 Jul 31;163:115287. doi: 10.1016/j.intimp.2025.115287. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a progressive and fatal lung disease, is predominantly driven by oxidative stress-induced alveolar epithelial cell (AEC) senescence. However, effective therapeutic strategies for IPF remain rudimentary. Here, we demonstrate that isorhapontigenin (ISO), a compound known to mitigate oxidative damage and mitochondrial lipid peroxidation, attenuates pulmonary fibrosis by targeting peroxiredoxin 2 (PRDX2). Utilizing bleomycin-induced murine models and TGF-β-treated BEAS-2B cells, we demonstrated that ISO markedly attenuate histopathological alterations and extracellular matrix deposition associated with pulmonary fibrosis, while concurrently mitigating alveolar epithelial cell senescence. Integrative analyses combining network pharmacology and proteomics identified PRDX2 as a principal molecular target of ISO. Further molecular docking studies and drug affinity responsive target stability (DARTS) assays revealed that ISO engages PRDX2 through STAT3, establishing a key molecular bridge for their interaction. Notably, LC-MS/MS-based proteomics combined with single-cell sequencing further revealed a pronounced downregulation of PRDX2 expression in fibrotic lung tissues. Knockdown of PRDX2 exacerbated fibrotic progression, underscoring its protective role in pulmonary homeostasis. Mechanistically, ISO alleviates oxidative stress and prevents AEC senescence through PRDX2 upregulation, thereby offering a novel therapeutic strategy for IPF. These findings not only establish PRDX2 as a pivotal regulator of pulmonary fibrosis but also highlight ISO as a promising therapeutic candidate for IPF treatment.

PMID:40749611 | DOI:10.1016/j.intimp.2025.115287

Respir Investig. 2025 Jul 31;63(5):955-963. doi: 10.1016/j.resinv.2025.07.014. Online ahead of print.

ABSTRACT

BACKGROUND: The prognostic utility of patient-reported outcomes (PROs) in mild to moderate fibrosing interstitial lung disease (FILD) remains insufficiently characterized.

METHODS: In this retrospective study, we examined the associations between PROs-Short-Form 36 (SF-36), Nagasaki University Respiratory Activities of Daily Living Questionnaire (NRADL), Hospital Anxiety and Depression Scale-Depression (HADS-D) and HADS-Anxiety (HADS-A)-and progression-free survival (PFS) in patients with FILD and a gender-age-physiology (GAP) score ≤5. We employed principal component analysis (PCA), hierarchical cluster analysis (HCA), and Cox proportional hazards modeling. PFS events were defined as a >10 % decline in forced vital capacity (FVC), >15 % decline in diffusing capacity for carbon monoxide (DLCO), acute exacerbation, or death from FILD.

RESULTS: Among 115 patients analyzed, PCA revealed that NRADL, select SF-36 subscales, and HADS-D correlated with age, gender, modified Medical Research Council scale, ILD-GAP score, FVC, DLCO, 6-min walk distance, and/or Chronic Obstructive Pulmonary Disease Assessment Test (CAT) score. HCA-based clustering of SF-36, NRADL, and HADS-D, and HADS-A-though not individual PRO measures-was independently associated with PFS. Additional independent predictors included lowest SpO2 during 6MWT, idiopathic pulmonary fibrosis diagnosis, and CAT score.

CONCLUSION: In patients with mild to moderate FILD, SF-36, NRADL, HADS-D, and HADS-A demonstrated associations with multiple clinical parameters. Clustering based on these PROs was significantly associated with PFS. These findings suggest that a multidimensional evaluation of health-related quality of life, activities of daily living, and mental status using PROs may offer valuable prognostic insights and support risk stratification in clinical practice.

PMID:40749361 | DOI:10.1016/j.resinv.2025.07.014

Nano Res. 2024 Oct;17(10):9095-9102. doi: 10.1007/s12274-024-6747-6. Epub 2024 Jun 27.

ABSTRACT

Activated fibroblasts are major mediators of pulmonary fibrosis. Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix (ECM) in the lung interstitial section. Therefore, fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis (IPF). Here, we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1 (LPA1) and the inflammatory pathway through tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) in fibroblasts. First, we synthesized a series of LPA1 antagonists, AM095 and AM966, derived amino lipids (LA lipids) which were formulated into LA-lipid nanoparticles (LA-LNPs) encapsulating mRNA. Specifically, LA5-LNPs, with AM966 head group and biodegradable acetal lipid tails, showed efficient A20 mRNA delivery to lung fibroblasts in vitro (80.2% ± 1.5%) and ex vivo (17.2% ± 0.4%). When treated to primary mouse lung fibroblasts (MLF), this formulation inhibited fibroblast migration and collagen production, thereby slowing the progression of IPF. Overall, LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.

PMID:40746964 | PMC:PMC12311867 | DOI:10.1007/s12274-024-6747-6

Front Mol Biosci. 2025 Jul 17;12:1647300. doi: 10.3389/fmolb.2025.1647300. eCollection 2025.

ABSTRACT

Pulmonary fibrosis (PF) is a fatal disease characterized by progressive fibrosis of lung tissue, with a key pathological feature of excessive accumulation of extracellular matrix. PF occurs from complicated origins, while emerging findings have suggested the involvement of the environmental factors in the risk of PF through epigenetic regulation. This article will discuss how recent advances in epigenetic alterations of DNA methylation, RNA methylation, histone modifications, and non-coding RNAs contribute to PF development through molecular mechanisms and cellular processes, including fibroblast-to-myofibroblast transition (FMT), epithelial-to-mesenchymal transition (EMT), alveolar epithelial cell injury and immune cell interactions in the past 5 years.

PMID:40746422 | PMC:PMC12310491 | DOI:10.3389/fmolb.2025.1647300

Noncoding RNA Res. 2025 Jul 3;15:51-64. doi: 10.1016/j.ncrna.2025.07.001. eCollection 2025 Dec.

ABSTRACT

AIMS: This study investigates how plasma exosomal miRNAs regulate core fucosylation (CF)-modified targets to influence autophagy and fibrosis in idiopathic pulmonary fibrosis (IPF), aiming to identify novel therapeutic strategies targeting dysregulated alveolar epithelial cell (AEC) autophagy.

MATERIALS AND METHODS: Plasma exosomes from IPF patients and healthy controls were isolated via ultracentrifugation, validated by TEM, nanoparticle tracking analysis (NTA), and Western blot (CD9/CD81). Exosomal miRNA profiling employed high-throughput sequencing, with TargetScan/miRanda predicting target genes. A549 and MLE-12 cells assessed exosome uptake (PKH67 labeling) and miRNA-mRNA interactions (dual-luciferase assays). CF modification was analyzed via immunoprecipitation/Western blot. In vivo validation used bleomycin (BLM)-induced fibrosis models in alveolar epithelial-specific FUT8-knockout (CKO) mice.

KEY FINDINGS: IPF plasma exosomes suppressed autophagy and exacerbated fibrosis in AECs. miR-15a-5p was markedly downregulated in IPF exosomes. Overexpression of miR-15a-5p reversed BLM-induced autophagy inhibition and fibrosis. Mechanistically, miR-15a-5p directly targeted IGF1R, a CF-modified protein. Reduced miR-15a-5p elevated IGF1R expression, activating PI3K/AKT to inhibit autophagy and promote fibrosis.

SIGNIFICANCE: This study identifies miR-15a-5p as a critical regulator of CF-modified IGF1R in IPF pathogenesis. Its downregulation drives PI3K/AKT-mediated autophagy suppression, accelerating fibrosis. Restoring miR-15a-5p or targeting IGF1R/PI3K/AKT signaling may offer novel therapeutic avenues for IPF.

PMID:40746334 | PMC:PMC12312048 | DOI:10.1016/j.ncrna.2025.07.001

Radiat Res. 2025 Aug 1. doi: 10.1667/RADE-23-00224.1. Online ahead of print.

ABSTRACT

Radiation-induced lung injury (RILI) includes early acute phase radiation pneumonitis (RP), and late chronic phase radiation-induced pulmonary fibrosis (RIPF). There is increasing evidence that ionizing radiation-induced cellular senescence is associated with pulmonary fibrosis. We have recently reported that biomarkers of senescence and, specifically, tyrosine kinase Fgr are induced in mouse RIPF, human idiopathic pulmonary fibrosis (IPF), and in human RIPF. We also reported that treatment with an Fgr inhibitor significantly reduced fibrosis of irradiated mouse lungs. Here, we investigated the association of senescence and tyrosine kinase Fgr in non-human primate (NHP) lung fibrosis and determined whether lung fibrosis can be predicted by analyzing the bronchoalveolar lavage (BAL) cells and fluid at early time points after irradiation. We found that markers of senescence (p16, p21) and expression of Fgr are induced in the lungs of NHP with RILI. That fibrosis can be predicted by analyzing BAL cells prior to the appearance of pulmonary fibrosis. We also induced senescence and expression of Fgr in irradiated normal human primary airway epithelial cells in vitro. In a transwell culture system, we established that senescent human airway epithelial cells induced the fibrosis biomarkers collagen1, collagen 3, and alpha-smooth-muscle actin in target human primary lung fibroblasts. Whole-thorax lung irradiated (WTLI) NHPs in this study developed moderate to severe pneumonitis and marked variations in the magnitude of RIPF as measured by trichrome staining. In BAL fluid that was collected from WTLI NHP, senescence-associated secretory proteins (SASP) were significantly induced, compared to the BAL fluid collected from control non-irradiated NHPs. Moreover, the levels of Fgr and biomarkers of senescence were significantly higher in NHPs with severely injured lungs compared to those with mildly or moderately injured lungs as indicated by fibrosis. Proinflammatory SASP cytokines increased to levels that correlated with the severity of RILI. The results show that senescent cells with induction of Fgr, and SASP cytokines are detectable in NHPs prior to RIPF and suggest that analysis of these proteins can predict the severity of RIPF prior to fully formed fibrosis.

PMID:40745576 | DOI:10.1667/RADE-23-00224.1

Eur Respir J. 2025 Jul 31:2500981. doi: 10.1183/13993003.00981-2025. Online ahead of print.

ABSTRACT

BACKGROUND: Predicting shorter life expectancy is crucial for prioritizing antifibrotic therapy in fibrotic lung diseases, where progression varies widely, from stability to rapid deterioration. This heterogeneity complicates treatment decisions, emphasizing the need for reliable baseline measures. This study focuses on leveraging artificial intelligence model to address heterogeneity in disease outcomes, focusing on mortality as the ultimate measure of disease trajectory.

METHODS: This retrospective study included 1744 anonymised patients who underwent high-resolution CT scanning. The AI model, SABRE (Smart Airway Biomarker Recognition Engine), was developed using data from patients with various lung diseases (n=460, including lung cancer, pneumonia, emphysema, and fibrosis). Then, 1284 high-resolution CT scans with evidence of diffuse FLD from the Australian IPF Registry and OSIC were used for clinical analyses. Airway branches were categorized and quantified by anatomic structures and volumes, followed by multivariable analysis to explore the associations between these categories and patients' progression and mortality, adjusting for disease severity or traditional measurements.

RESULTS: Cox regression identified SABRE-based variables as independent predictors of mortality and progression, even adjusting for disease severity (fibrosis extent, traction bronchiectasis extent, and ILD extent), traditional measures (FVC%, DLCO%, and CPI), and previously reported deep learning algorithms for fibrosis quantification and morphological analysis. Combining SABRE with DLCO significantly improved prognosis utility, yielding an AUC of 0.852 at the first year and a C-index of 0.752.

CONCLUSIONS: SABRE-based variables capture prognostic signals beyond that provided by traditional measurements, disease severity scores, and established AI-based methods, reflecting the progressiveness and pathogenesis of the disease.

PMID:40744692 | DOI:10.1183/13993003.00981-2025

PLoS One. 2025 Jul 31;20(7):e0328250. doi: 10.1371/journal.pone.0328250. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening interstitial lung disease whose pathogenesis remains unclear. There is evidence showing the possible role of CD8+ T cells in the pathogenesis of IPF and the correlation with the clinical symptoms of IPF. In order to further explore the role of CD8+ T cells in IPF, we screened CD8+ T cell related genes (CRG) that are associated with IPF prognosis, and established the molecular typing characteristics of IPF. Subsequently, CXCR4, GPR56 and PAK1 were screened as independent prognostic factors. Expression profiles and multivariate analysis coefficients were used to establish and validate prognostic features of IPF. Immuno-infiltration characteristics of the established feature were also analyzed. Subsequent in vitro experiments verified the abnormal expressions of three independent prognostic factors in TGF-β1 treated IPF model at protein and mRNA levels. Our findings shed new light on the important role of CD8+ T cells in the pathogenesis of IPF and provide potential targets for predicting prognosis and possible future clinical applications.

PMID:40743122 | DOI:10.1371/journal.pone.0328250

Front Med (Lausanne). 2025 Jul 16;12:1611304. doi: 10.3389/fmed.2025.1611304. eCollection 2025.

ABSTRACT

BACKGROUND: Lung organoids have emerged as a promising tool for studying lung development, function, and disease pathology. The present study aimed to analyze the current status and development trends of lung organoid research over the past years, present visual representations, and provide references for future research directions using bibliometric analysis.

METHODS: Information on articles on lung organoids extracted from the Web of Science Core Collection, such as year of publication, journal, country, institution, author, and keywords, was analyzed. R, VOSviewer, and SCImago Graphica were used to visualize publication trends, co-authorship analysis, co-occurrence analysis, and hotspot evolution.

RESULTS: The number of global publications has increased from 1 in 2011 to 929 in 2024. The Nature produced the highest number of citations (2,675 citations). The United States (8,155 citations and 281 publications), University Medical Center Utrecht (2083 citations and 11 publications), and Clevers H (2,711 citations and 21 publications) were the most influential countries, institutions, and authors, respectively. Co-occurrence cluster analysis of the top 54 keywords formed four clusters: (1) idiopathic pulmonary fibrosis, (2) lung cancer, (3) cystic fibrosis, (4) COVID-19.

CONCLUSION: Overall, research on lung organoids continues to increase. The United States of America and the Netherlands dominated global studies. The analysis of pulmonary fibrosis, lung cancer and COVID-19 occupied a prominent position of research in this area. The research hotspots for lung organoids are disease model and microphysiological systems. Standardization, accurate disease modeling, and ethics and safety remain pressing challenges that need to be addressed in this field.

PMID:40740941 | PMC:PMC12307212 | DOI:10.3389/fmed.2025.1611304

Aging Cell. 2025 Jul 30:e70179. doi: 10.1111/acel.70179. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) tail at different sites of 3' UTR and generates transcript isoforms with different 3' UTR lengths. We found that NUDT21 was downregulated in aging and fibrotic lungs, particularly at the fibrotic foci of IPF lungs known to have abundant senescent myofibroblasts and collagens. NUDT21 knockdown in normal lung fibroblasts promoted the 3' UTR shortening of several STAT3 signaling components and enhanced STAT3 phosphorylation and the expression of several SASPs, including interleukins, collagens, and matrix metalloproteinases (MMPs). Moreover, NUDT21 downregulation may be associated with increased fibroblast senescence and abnormal mitochondrial function. Importantly, mice with Nudt21 deletion in Col1a1 expressing cells aggravated bleomycin-induced pulmonary fibrosis. Taking together, our study demonstrated an important role of NUDT21-mediated APA in regulating SASP expression and fibroblast senescence that could contribute to the pathogenesis of IPF.

PMID:40738116 | DOI:10.1111/acel.70179