Front Pharmacol. 2025 May 2;16:1506518. doi: 10.3389/fphar.2025.1506518. eCollection 2025.

ABSTRACT

INTRODUCTION: Senescent cells (SCs) accumulate with age and play a causative role in age-related diseases, such as idiopathic pulmonary fibrosis (IPF). Clearance of SCs attenuates lung fibrogenesis and favors fibrosis resolution, suggesting that targeting of SCs is recognized as a promising therapeutic approach for IPF. Isothiocyanates (ITCs) are natural compounds with anticancer and anti-aging properties, but their role in IPF remains unclear. The aim of our study to investigate whether benzyl isothiocyanate (BITC), a type of ITCs, can act as a senolytic agent thereby attenuating pulmonary fibrosis in aged mice.

METHODS: Primary lung fibroblasts from IPF patients and controls were cultured and treated with various ITCs to identify potential senolytic agents. Senescence-associated β-galactosidase staining, Cell viability assays, Annexin V/PI double staining, Caspase 3 activity assay, Western blot analysis, and qPCR were performed to evaluate senescence markers, cell viability, and apoptosis-related proteins after BITC treatment of senescent IPF lung fibroblasts in vitro. HE staining, Masson staining, Hydroxyproline assay, and Western blot analysis were used to assess the pathological progress, collagen content of lung tissues, and fibrotic gene expression changes after BITC treatment in C57BL/6 aged mice.

RESULTS: Using senescent IPF fibroblasts, we screened and identified BITC as a potent senolytic drug. We show that BITC selectively induces apoptosis in senescent IPF fibroblasts by targeting AKT signal pathway. Intraperitoneal administration of BITC to an age-related lung fibrosis mouse model effectively depleted senescent lung fibroblasts and reversed persistent pulmonary fibrosis.

DISCUSSION: Our study reveals that BITC may be a promising therapeutic option for IPF and other age-related disease that progress with the accumulation of senescent fibroblasts.

PMID:40385483 | PMC:PMC12081420 | DOI:10.3389/fphar.2025.1506518

World J Clin Cases. 2025 May 16;13(14):98769. doi: 10.12998/wjcc.v13.i14.98769.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has a poor prognosis if left untreated; therefore, early treatment with pirfenidone is crucial. Lei et al conducted a retrospective analysis to evaluate the effectiveness of early pirfenidone treatment on lung function in 113 patients with IPF. In addition to other research, pirfenidone has demonstrated efficacy in patients at all stages of IPF once correct diagnosis has been made. In advanced IPF, we include the requirement for pirfenidone. Therefore, it is essential to choose an appropriate method of administration method, such as inhalation. This may circumvent the drawbacks of the high cost and possible adverse effects of this drug.

PMID:40385293 | PMC:PMC11752435 | DOI:10.12998/wjcc.v13.i14.98769

J Control Release. 2025 May 16:113862. doi: 10.1016/j.jconrel.2025.113862. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) exhibits extremely high mortality rates. Targeted therapy, which utilizes specific drugs or other substances to identify and attack specific molecular targets in the lesion, holds promise as a potent means of treating IPF. M2 macrophages have been shown to express high levels of osteopontin (OPN) early in the onset of IPF and sustain this high expression to promote the progression of IPF. Intervention in OPN expression can effectively impede the development of fibrosis. While the technology for targeting proteins with siRNA has become increasingly mature, the targeted delivery of siRNA to resident M2 macrophages in the lungs remains challenging. In this study, we developed an engineered self-assembling OPN siRNA carrier complex based on a metal-polyphenol network (luteolin-Zr) and PEG conjugated with an M2 macrophage-targeting peptide (Pery-PEG-M2), termed siOPN@LuZ-M2, for the treatment of pulmonary fibrosis. Consequently, significant therapeutic effects were observed in both bleomycin-induced pulmonary fibrosis mouse models and human precision-cut lung slices (hPCLS) models. Importantly, luteolin, which is slowly released from siOPN@LuZ-M2 within cells, can gradually accumulate in fibrotic lung tissue, exerting an anti-inflammatory effect and further enhancing the treatment of IPF. It is worth mentioning that siOPN@LuZ-M2 can be labeled with 89Zr, allowing for the detection of its in vivo distribution and metabolic behavior via PET-CT. This study presents a promising new image-guided molecular targeting strategy for the treatment of fibrosis.

PMID:40383161 | DOI:10.1016/j.jconrel.2025.113862

Heart Lung. 2025 May 17;73:114-122. doi: 10.1016/j.hrtlng.2025.05.008. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, potentially fatal lung disorder characterized by scarring, leading to reduced lung function and respiratory failure. Nintedanib, a tyrosine kinase inhibitor, shows potential in slowing IPF progression, but uncertainties remain about its long-term efficacy and safety.

OBJECTIVE: To evaluate the efficacy and safety of Nintedanib in idiopathic pulmonary fibrosis.

METHODS: A comprehensive literature search was conducted across PubMed, Cochrane, Scopus, Embase, and ClinicalTrials.gov from inception to August 2024, selecting studies based on predefined eligibility criteria. Dichotomous outcomes were pooled as risk ratios (RR) and continuous outcomes as mean differences (MD), both with 95% confidence intervals (CI), using random-effects models to account for potential heterogeneity. Heterogeneity was assessed using I² and X² statistics, with a p-value of <0.05 considered statistically significant. All calculations were performed using RevMan 5.4.

RESULTS: This meta-analysis included 4 randomized controlled trials with 1,665 patients, 79.7% of whom were male smokers. There was no significant difference in IPF progression (RR=0.61, 95% CI 0.34-1.08, I²=41%) or in nasopharyngitis (RR=0.82, 95% CI 0.62-1.08, I²=0%), cough (RR=0.98, 95% CI 0.71-1.33, I²=0%), bronchitis (RR=0.90, 95% CI 0.63-1.28, I²=0%), respiratory infections (RR=1.01, 95% CI 0.59-1.75, I²=0%), dyspnea (RR=0.68, 95% CI 0.46-1.00, I²=0%), or cardiac disorders (RR=0.89, 95% CI 0.50-1.58, I²=0%), indicating nintedanib does not notably alter these risks. However, nintedanib significantly increased gastrointestinal adverse events, potentially affecting adherence and quality of life.

CONCLUSION: Nintedanib shows promise in slowing disease progression but carries a higher risk of adverse events. Limited sample sizes and short follow-up necessitate larger studies to confirm its efficacy and safety.

PMID:40382966 | DOI:10.1016/j.hrtlng.2025.05.008

Cell Signal. 2025 May 15:111867. doi: 10.1016/j.cellsig.2025.111867. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by irreversible scarring of the lungs, predominantly affecting older adults. The limited therapeutic options available are largely due to an insufficient understanding of IPF etiology and pathogenesis. This study investigated potential biomarkers to enhance IPF diagnosis and treatment strategies. Through single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing analyses of public datasets, four hub genes-FTH1, FABP5, DCXR, and IGFBP7-were identified as strongly associated with IPF. Subsequent validation in in vivo and in vitro models confirmed IGFBP7 as a novel biomarker. Double immunofluorescence staining and scRNA-seq analysis revealed that IGFBP7 expression is elevated in IPF epithelial cells. IGFBP7 shows potential for early diagnosis of IPF and can differentiate IPF from other diseases. Gene set enrichment analysis revealed the involvement of IGFBP7 in IPF pathogenesis, particularly through its strong connection to the TGF-β signaling pathway, which drives inflammation and fibrosis. In vitro studies with the TGF-β inhibitor SB431542 showed that inhibition of the TGF-β pathway significantly reduced IGFBP7 expression. Furthermore, IGFBP7 knockdown decreased the expression of markers associated with epithelial-mesenchymal transition and fibrosis while suppressing TGF-β1 expression. These results suggest that IGFBP7 forms a positive feedback loop with TGF-β1. In conclusion, this research identified IGFBP7 as a promising biomarker with significant diagnostic and therapeutic potential for IPF. These insights pave the way for improved diagnostics and the development of targeted antifibrosis therapies, while deepening our understanding of IPF mechanisms.

PMID:40381971 | DOI:10.1016/j.cellsig.2025.111867

Lancet Rheumatol. 2025 May 14:S2665-9913(25)00026-8. doi: 10.1016/S2665-9913(25)00026-8. Online ahead of print.

ABSTRACT

BACKGROUND: In patients with systemic sclerosis, it is common practice to treat interstitial lung disease (ILD) in patients in whom progression has already occurred. We sought to clarify whether observed progression of systemic sclerosis-associated ILD confers risk for subsequent progression.

METHODS: In this multicentre observational cohort study, based on an analysis of prospectively collected data, we included patients with systemic sclerosis-associated ILD aged 18 years or older at diagnosis, who fulfilled the 2013 American College of Rheumatology-European Association of Alliances in Rheumatology systemic sclerosis classification criteria. The main cohort (diagnosed between January 2001 and December 2019) was consecutively followed up annually over 4 years at the Department of Rheumatology at the Oslo University Hospital, Norway, and the Department of Rheumatology at the University Hospital Zurich, Switzerland. We applied four definitions of ILD progression: the primary definition was forced vital capacity (FVC) decline of 5% or more, and secondary definitions included FVC decline of 10% or more, progressive pulmonary fibrosis (PPF), and progressive fibrosing ILD (PF-ILD). We applied these definitions at each annual visit after the first (visit 1). We validated our findings in an enriched cohort that included patients from the main cohort with systemic sclerosis-associated ILD and short disease duration of less than 3 years along with patients diagnosed between January 2003 and September 2019 from the Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA. Multivariable logistic regression analyses were applied to predict ILD progression and its effect on mortality. There was no involvement of people with lived experience in this study.

FINDINGS: Of 231 patients with systemic sclerosis-associated ILD from the main cohort (mean age 48·0 years [SD 14·6], 176 [76%] female and 55 [24%] male), 71 (31%) had ILD progression as defined by an FVC decline of 5% or more between visit 1 and visit 2, 38 (16%) as defined by an FVC decline of 10% or more, 39 (17%) as defined by PPF, and 89 (39%) defined by PF-ILD. In multivariable logistic regression analyses, adjusted for risk factors for progressive systemic sclerosis-associated ILD and immunosuppressive treatment, we found that ILD progression, defined by FVC decline of 5% or more, from visit 1 to visit 2 reduced the risk for further progression from visit 2 to visit 3 (odds ratio [OR] 0·28 [95% CI 0·12-0·63]; p=0·002) and that there was no risk for subsequent progression using the other definitions (FVC decline of ≥10%: 0·57 [0·16-1·99; p=0·38]; PPF: 0·93 [0·39-2·22; p=0·88]; and PF-ILD: 0·69 [0·35-1·36]; p=0·28]). Using the primary definition of progression, we found the same results in the enriched systemic sclerosis-associated ILD cohort, wherein 41 (34%) of 121 patients had progression defined by an FVC decline of 5% or more (OR 0·22 [95% CI 0·06-0·87]; p=0·031). FVC decline of 5% or more was significantly associated with mortality (hazard ratio 1·66 [95% CI 1·05-2·62]; p=0·030) adjusted for other risk factors.

INTERPRETATION: Systemic sclerosis-associated ILD progression does not predict further ILD progression at the next annual follow-up visit, even in an enriched population, but progression was associated with mortality. These results have implications for clinical practice because they support a paradigm shift in treatment strategy, advocating for initiating therapy in patients at risk of progression. Further research is needed to confirm these findings.

FUNDING: None.

TRANSLATIONS: For the German and Norwegian translations of the abstract see Supplementary Materials section.

PMID:40381640 | DOI:10.1016/S2665-9913(25)00026-8

Respir Res. 2025 May 16;26(1):188. doi: 10.1186/s12931-025-03264-z.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating age-related disease with unknown causes and limited effective treatment. Dysregulation of Alveolar Type 2 (AT2) cells facilitates the initiation of IPF. While differentiation of AT2 into AT1 is necessary for restoring alveolar epithelium. Delta-like non-canonical Notch ligand 1 (DLK1) is a paternally imprinted gene that controls stem cell differentiation. However, the role of DLK1 on AT2 during lung fibrosis remains unclear.

METHODS: Lung specimens from 11 patients with IPF or contemporaneous non-IPF controls were collected to determine DLK1 expression. The murine model of bleomycin (BLM) -induced pulmonary fibrosis and cell models of transforming growth factor-beta (TGF-β)-treated A549, MRC5 or primary lung fibroblasts (PLFs) were established. Epithelial DLK1 knockdown mice were constructed by an alveolar epithelial -specific adeno-associated virus (AAV) 6 vector system. Besides, primary AT2 cells were isolated from SPC-EGFP mice and cultured in 2D and 3D organoids.

RESULTS: In the present study, we found that DLK1, predominantly expressed in AT2 cells, was upregulated in both IPF lungs and the murine fibrotic lung induced by BLM. AAV-mediated epithelial-specific knockdown of DLK1 promoted the proliferation and differentiation of AT2 into AT1 and alleviated the established lung fibrosis in murine BLM-induced models. In addition, recombinant DLK1 inhibited the renewal of AT2 and aggravated TGF-β-induced fibrosis in vitro, which can be rescued by si-DLK1 intervention. Mechanically, conditional knockdown of DLK1 upregulated TTF-1, a transcriptional factor that controls AT2 differentiation via CLDN6.

CONCLUSION: DLK1 inhibition regulates AT2 differentiation and contributes to the mitigation of established fibrosis via TTF-1/CLDN6 pathway, which suggests that DLK1 may be a therapeutic target for IPF.

PMID:40380180 | DOI:10.1186/s12931-025-03264-z

Aging (Albany NY). 2025 May 15;17. doi: 10.18632/aging.206250. Online ahead of print.

ABSTRACT

BACKGROUND: Both genetic and environmental factors can influence idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) development. The gut microbiota plays crucial roles in maintaining tissue homeostasis. Dysregulation of the gut microbiota can result in disease. However, whether the alteration of the gut microbiota influences IPF and COPD remains unknown.

RESEARCH QUESTION: What is the causal relationship between IPF, COPD and the gut microbiota-related metabolic pathways? What are the potential intermediate mediators in this relationship?

STUDY DESIGN AND METHODS: Intersect the gut microbiota and its metabolic pathways associated with IPF and COPD. Utilizing summary data from GWAS in public databases, a two-sample Mendelian randomization (MR) analysis was conducted on the gut microbiota-related metabolic pathway, the aspartate superpathway, in relation to IPF and COPD. Furthermore, we employed a two-step MR to quantify the proportion of influence mediated by monocytes and cDCs on the aspartate superpathway in relation to IPF and COPD.

RESULTS: The MR analysis found that the aspartate superpathway decreased the risk of developing IPF and COPD. Monocytes and cDCs acted as intermediary substances, participating in this with influence proportions of 7.88% and 6.27%, respectively.

INTERPRETATION: There is a causal link between the gut microbiota-related metabolic pathway, the aspartate superpathway, and IPF and COPD, where the influence is partially mediated by monocytes and cDCs. In clinical practice, we increase the focus on gut microbiota-mediated immune cells in relation to IPF and COPD.

PMID:40378019 | DOI:10.18632/aging.206250

J Respir Biol Transl Med. 2025 Mar;2(1):10002. doi: 10.70322/jrbtm.2025.10002. Epub 2025 Mar 24.

ABSTRACT

Pulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. A previous genome-wide association study (GWAS) with Affymetrix microarray analysis data exhibited elevated histidine triad nucleotide-binding protein 3 (HINT3) in the lung samples of PAH compared to control subjects (failed donors, FD) and the positive correlations of HINT3 with deubiquitinase USP11 and B-cell lymphoma 2 (BCL2). In this study, we aim to investigate the roles and interplay of USP11 and HINT3 in the apoptosis resistance of PAH. The levels of USP11 and HINT3 were increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice. USP11 and HINT3 interacted physically, as shown by co-immunoprecipitation (co-IP) assay in human pulmonary arterial endothelial cells (HPAECs). HINT3 was degraded by polyubiquitination, which was reversed by USP11. Furthermore, HINT3 interacted with the anti-apoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, the knockdown of HINT3 function led to a depletion of BCL2. Thus, we conclude that USP11 stabilizes HINT3 activation, which contributes to endothelial apoptosis-resistance of pulmonary arterial endothelial cells in PAH. This can potentially be a novel therapeutic target for ubiquitination modulators for PAH.

PMID:40376595 | PMC:PMC12080269 | DOI:10.70322/jrbtm.2025.10002

Respir Res. 2025 May 15;26(1):185. doi: 10.1186/s12931-025-03227-4.

NO ABSTRACT

PMID:40375119 | DOI:10.1186/s12931-025-03227-4

Sci Rep. 2025 May 15;15(1):16969. doi: 10.1038/s41598-025-01459-4.

ABSTRACT

Objective Idiopathic pulmonary fibrosis (IPF), which radiologically/pathologically manifests mainly as usual interstitial pneumonia (UIP), is easily confused with chronic hypersensitivity pneumonitis (CHP) and collagenous vascular disease in clinical settings, affecting the physician's diagnosis and treatment. Accurate identification of IPF from various diseases presenting as UIP is essential for effective diagnosis and therapy. Methods Gene expression data of CHP, IPF, and rheumatoid arthritis-UIP samples were downloaded from the GEO database, and specific biomarkers were identified to differentiate idiopathic UIP/IPF from secondary UIP. We compared gene expression of specific biomarkers between control, secondary UIP, and IPF groups. The mechanism of specific biomarkers in PF was explored by immunohistochemistry, quantitative polymerase chain reaction, immunofluorescence, and flow cytometry. Results We identified integrin alpha V (ITGAV) as a specific biomarker for distinguishing IPF from secondary UIP. We observed a gradual increase in ITGAV expression across the control, secondary UIP, and IPF groups. Animal studies indicated that the elevated expression of ITGAV in various immune cells, particularly in monocyte-derived macrophages, contributed to the development of PF. Conclusion ITGAV is a specific biomarker linked to the pathogenesis of IPF. The identification of ITGAV provides new perspectives for clinical diagnosis, mechanistic studies and new drug development in IPF.

PMID:40374686 | DOI:10.1038/s41598-025-01459-4

Cell Signal. 2025 May 13:111868. doi: 10.1016/j.cellsig.2025.111868. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder marked by deteriorating dyspnea and declining pulmonary function. Despite its rising prevalence and incidence, therapeutic options remain limited. PTEN-induced kinase 1 (PINK1), known for its role in PINK1/Parkin-dependent mitophagy, contributes to the pathogenesis of various lung diseases. In this study, we elucidate a previously unrecognized mechanism of PINK1, beyond its canonical mitophagy function, during pulmonary fibrosis. We established a bleomycin (BLM)-induced pulmonary fibrosis model in Pink1 knockout (Pink1-/-) mice and treated BEAS-2B cells with transforming growth factor-beta 1 (TGF-β1) to simulate the microenvironment of pulmonary fibrosis. A significant elevation in PINK1 expression was observed in vivo and in vitro systems. While PINK1/Parkin-dependent mitophagy was activated, mitophagy mediated by BCL2-interacting protein 3 (BNIP3) and FUN14 domain-containing 1 (FUNDC1) was suppressed. Further experiments in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-treated PINK1 knockout (KO) HEK293 cells and YFP-Parkin-expressing HeLa cells demonstrated that PINK1 deficiency enhanced BNIP3- and FUNDC1-mediated mitophagy, whereas PINK1 overexpression inhibited it. Moreover, dual BNIP3/FUNDC1 knockdown significantly reversed the anti-apoptotic effect of PINK1 KO. We conclude that PINK1 deficiency promotes the clearance of damaged mitochondria via BNIP3/FUNDC1 upregulation, preserving mitochondrial homeostasis, mitigating alveolar epithelial injury, and attenuating fibrosis. Thus, PINK1 may inhibit BNIP3- and FUNDC1-mediated mitophagy besides driving PINK1-dependent mitophagy during pulmonary fibrosis.

PMID:40373838 | DOI:10.1016/j.cellsig.2025.111868

Zentralbl Chir. 2025 May 15. doi: 10.1055/a-2563-3691. Online ahead of print.

ABSTRACT

Lung transplantation has evolved continuously since its first successful procedures in the 1960 s. The current guidelines from the International Society for Heart and Lung Transplantation (ISHLT) emphasise increasingly individualised patient assessment, which, in addition to the underlying lung disease, considers factors such as comorbidities, frailty, age, and social aspects. The expanded indications for lung transplantation are reflected in the refined risk assessment, which particularly includes patients with advanced chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary arterial hypertension (PAH). Furthermore, the criteria for patients with a history of cancer and those with infections such as HIV or multidrug-resistant organisms have been made more flexible, leading to a more inclusive transplantation policy. A key focus is on early transplant counselling, allowing patients the opportunity for transplantation before they develop acute exacerbations. These updated guidelines aim to maximise both the survival rates and the quality of life of transplant patients, through differentiated and risk-adjusted decision-making.

PMID:40373816 | DOI:10.1055/a-2563-3691

Sci Rep. 2025 May 14;15(1):16825. doi: 10.1038/s41598-025-99792-1.

ABSTRACT

The coexistence of chronic fibrosing idiopathic interstitial pneumonia (cf-IIP) and lung cancer (LC) in the same patient raises many doubts regarding patient prognosis and complicates decision-making in multidisciplinary thoracic committees. To provide new insights into the management and prognosis of patients with cf-IIP, we assessed the sociodemographic and clinical differences between patients with and without LC to evaluate their role in their mortality. Other factors were also studied. A longitudinal study was conducted from January 1, 2001, to December 31, 2020, in our hospital. All patients who attended the interstitial lung disease multidisciplinary unit and had a medical diagnosis of cf-IIP were included. The primary outcome was all-cause mortality. The independent variable was the presence of LC. Covariates: sociodemographic, clinical, and therapeutic variables. The mortality rate (MR) was expressed per 1000 patient-years with a 95% confidence interval (CI). Cox multiple regression analysis examined the influence of LC and other covariates on mortality. The results are expressed as hazard ratios (HRs) with CIs. A total of 313 patients with cf-IIP were included, with a follow-up of 1589.6 patient-years. There were 209 (66.8%) deaths. The MR was 131.5 (114.8-150.6), and 50% of patients died at 5.58 years from cf-IIP diagnosis. After adjusting for confounders, LC was associated with a significantly increased risk of mortality (HR 4.11; 2.50-6.77; p = 0.000), whereas antifibrotic treatment was the only factor that decreased the risk of mortality (HR 0.60; 0.43-0.84; p = 0.003). The prevalence of LC was 15.3%. The most common histopathological type was squamous cell carcinoma (39.6%). At diagnosis, 68.7% of LC cases were in stages III-IV. The most widely used treatment was chemotherapy and its combination (43.7%). Patients with cf-IIP who developed LC had a fourfold increased risk of mortality and shorter mean survival (2 years vs. 6 years) compared with those without LC. Therefore, we recommend LC screening in these patients.

PMID:40369244 | DOI:10.1038/s41598-025-99792-1

Acta Pharmacol Sin. 2025 May 14. doi: 10.1038/s41401-025-01558-y. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by complex aetiologies involving the accumulation of inflammatory cells, such as macrophages, in the alveoli. This process is driven by uncontrolled extracellular matrix (ECM) deposition and the development of fibrous connective tissues. Here, we observed that the mRNA expression of Ffar1, the gene encoding G protein-coupled receptor 40 (GPR40), is repressed, while Cd36 is increased in the bronchoalveolar lavage fluid (BALF), which is predominantly composed of alveolar macrophages, of IPF patients. Furthermore, the GPR40 protein was found to be largely adhered to macrophages and was pathologically downregulated in the lungs of bleomycin (BLM)-induced PF model mice (PF mice) compared with those of control mice. Specific knockdown of GPR40 in pulmonary macrophages by adeno-associated virus 9-F4/80-shGPR40 (AAV9-shGPR40) exacerbated the fibrotic phenotype in the PF mice, and activation of GPR40 by its determined agonist compound SC (1,3-dihydroxy-8-methoxy-9H-xanthen-9-one) effectively protected the PF mice from pathological exacerbation. Moreover, Ffar1 or Cd36 gene knockout mouse-based assays were performed to explore the mechanism underlying the regulation of GPR40 activation in pulmonary macrophages with compound SC as a probe. We found that compound SC mitigated pulmonary fibrosis progression by preventing M2 macrophage polarization from exerting profibrotic effects through the GPR40/PKD1/CD36 axis. Our results strongly support the therapeutic potential of targeting intrinsic GPR40 activation in pulmonary macrophages for IPF and highlight the potential of compound SC in treating this disease.

PMID:40369224 | DOI:10.1038/s41401-025-01558-y

Sci Rep. 2025 May 14;15(1):16801. doi: 10.1038/s41598-025-01759-9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease. Recent evidence suggests that the pathogenesis of IPF may involve abnormalities in mitochondrial energy metabolism. This study aimed to identify mitochondrial energy metabolism related differentially expressed genes (MEMRDEGs) and to elucidate their potential mechanistic involvement in IPF. We employed a multistep bioinformatics approach, including data extraction from the Gene Expression Omnibus database, removal of batch effects, and normalization and differential gene expression analyses. We then conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment, and gene set enrichment analyses. A protein-protein interaction network was constructed from the STRING database, and hub genes were identified. Receiver operating characteristic curve analysis was performed to evaluate immune infiltration. Our integrated analysis of IPF datasets identified 25 MEMRDEGs. Nine hub genes emerged as central to mitochondrial energy metabolism in IPF. COX5A, EHHADH, and SDHB are potential biomarkers for diagnosing IPF with high accuracy. Single-sample gene set enrichment analysis revealed significant differences in the abundances of specertainfic immune cell types between IPF samples and controls. In conclusion, COX5A, EHHADH, and SDHB are potential biomarkers for the high-accuracy diagnosis of IPF. These findings pave the way for further investigations into the molecular mechanisms underlying IPF.

PMID:40369105 | DOI:10.1038/s41598-025-01759-9

Intern Med. 2025;64(10):1552-1562. doi: 10.2169/internalmedicine.4493-24. Epub 2025 May 15.

ABSTRACT

Nintedanib inhibits disease progression in patients with idiopathic pulmonary fibrosis (IPF) and dramatically improves the lung function in patients known to be super-responders (SRs). However, there are no reports on quantitative high-resolution computed tomography (HRCT), and the HRCT imaging characteristics of SRs remain unknown. We herein present the case of a 66-year-old man with IPF who was a SR to nintedanib treatment, which showed a marked improvement compared to other patients with IPF upon quantitative HRCT evaluation using the artificial intelligence (AI) software 3D Slicer. This study is worth reporting because a quantitative HRCT assessment using AI may be necessary to understand the SR characteristics.

PMID:40368830 | DOI:10.2169/internalmedicine.4493-24

Intern Med. 2025 May 15. doi: 10.2169/internalmedicine.5575-25. Online ahead of print.

NO ABSTRACT

PMID:40368795 | DOI:10.2169/internalmedicine.5575-25

Intern Med. 2025 May 15. doi: 10.2169/internalmedicine.5447-25. Online ahead of print.

ABSTRACT

Objectives To analyze the influence of age of the onset on myositis organ damage and to identify the factors influencing myositis organ damage, as clinical manifestations of myopathies differ by the age of onset and the background of patients. Methods Factors influencing organ damage [SLICC/ACR Damage Index (SDI)] were identified using the Japanese multicenter myositis registry (MYKO, n=220). Factors influencing organ damage were identified using a multivariate analysis. SDI was compared among juvenile-onset (<20 years old), adolescent-onset (20-64 years), and elderly-onset (>64 years) groups. Results There was a correlation between the age at onset and the SDI score (Spearman's rank correlation coefficient ρ=0.28). Elderly patients exhibited more widespread organ damage, including neuropsychiatric, renal, pulmonary, cardiovascular, peripheral vascular, gastrointestinal, skin, and diabetes, whereas juvenile-onset patients exhibited musculoskeletal damage. Adolescent-onset patients had the lowest incidence of ocular and malignant damage. A regression analysis revealed that an older onset age (coefficient, β=0.03), longer disease duration (β=0.05), and total dose of glucocorticoid (β=3.35x10-5) influenced SDI. After adjusting for disease duration, the influences of anti-MDA5 [hazard ratio (95% confidence interval), 4.47 (2.17-9.21)] on pulmonary fibrosis and a history of steroid pulse [2.16 (1.16-4.05)] on muscle atrophy or weakness were shown. Conclusions There were associations between the age of onset and autoantibodies with myositis organ damage. Musculoskeletal damage was greater in patients with a juvenile onset. An older age of onset is associated with severe organ damage. These findings highlight the importance of considering the age of onset and autoantibodies for assessing the prognosis and developing treatment plans for myopathies.

PMID:40368794 | DOI:10.2169/internalmedicine.5447-25

Breathe (Sheff). 2025 May 13;21(2):240261. doi: 10.1183/20734735.0261-2024. eCollection 2025 Apr.

ABSTRACT

This review summarises some of the key features of interstitial lung diseases (ILDs) from a translational science point of view and brings insights into potential therapeutic options. Genetic predisposition and environmental factors like smoking, pollution and infections significantly impact the onset, progression and treatment response in ILDs, highlighting the need for personalised management. Fibroblasts are central to ILD pathology, influencing the tissue microenvironment, immune cell interactions and extracellular matrix (ECM) production, making them critical therapeutic targets. Monocyte-derived M2 macrophages drive fibrosis in idiopathic pulmonary fibrosis by secreting cytokines and remodelling the ECM. Understanding macrophage subtypes and their dynamics offers new therapeutic possibilities. Chronic type 2 immunity contributes to fibrosis, emphasising the need to enhance protective markers in order to even out the balance shift of pathological immune responses in ILD treatments. Serum biomarkers like Krebs von den Lungen-6 (KL-6), surfactant protein (SFTP) D, matrix metalloproteinase-7 (MMP-7), and C-C motif chemokine ligand (CCL)-18 are valuable for diagnosing and predicting ILD progression, although more research is needed for clinical application. Animal models, especially bleomycin-based models, offer insights into ILD pathology, but challenges like lung hyperinflation highlight the need for careful model selection and translational research to bridge preclinical and clinical findings.

PMID:40365095 | PMC:PMC12070197 | DOI:10.1183/20734735.0261-2024