Cell Death Discov. 2025 Apr 12;11(1):168. doi: 10.1038/s41420-025-02444-6.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic interstitial lung disease with unclear underlying pathogenic mechanisms. Dysbiosis of the lung microbiota is believed to be associated with the development of fibrosis; however, the roles of the microbiome in the respiratory functions of hosts with IPF remain poorly understood. To investigate the relationship between the lung microbiome and the pathological processes of idiopathic pulmonary fibrosis under laboratory conditions, C57BL/6 J mice were exposed to bleomycin and observed at 7, 14, 21, and 28 days post-exposure. 16S rDNA analysis revealed that the lung microbial community exhibited dysbiosis in the bleomycin-induced pulmonary fibrosis model, characterized by an abnormally high proportion of Klebsiella quasipneumoniae (K. quasipneumoniae), as confirmed by RNA fluorescence in situ hybridization. Throughout the progression of experimental pulmonary fibrosis, Tax4Fun analysis indicated that the abundance of K. quasipneumoniae differed significantly between model mice and control mice, correlating with the sustained activation of reactive oxygen species (ROS) pathways. Importantly, the dysbiosis of K. quasipneumoniae may serve as a critical factor triggering increased ROS levels, accompanied by macrophage mitophagy, ultimately leading to the overexpression of TGF-β1, a key player in the pathogenesis of pulmonary fibrosis. These findings suggest that lung microbiota dysbiosis exacerbates the progression of bleomycin-induced pulmonary fibrosis related to macrophage mitophagy.

PMID:40221415 | DOI:10.1038/s41420-025-02444-6

J Clin Med. 2025 Mar 24;14(7):2205. doi: 10.3390/jcm14072205.

ABSTRACT

In recent years, several studies have examined the impact of sleep-disordered breathing (SBD) on the quality of life and prognosis of patients with idiopathic pulmonary fibrosis (IPF). Among these disorders, obstructive sleep apnea (OSA) and nocturnal hypoxemia (NH) are the most prevalent and extensively studied, whereas central sleep apnea (CSA) has only been documented in recent research. The mechanisms underlying the relationship between IPF and SBDs are complex and remain an area of active investigation. Despite growing recognition of SBDs in IPF, no standardized guidelines exist for their management and treatment, particularly in a population characterized by distinct structural pulmonary abnormalities. This review outlines the pathophysiological connections between sleep-breathing disorders (SBDs) and idiopathic pulmonary fibrosis (IPF), as well as current therapeutic options. A comprehensive literature search using PubMed identified relevant studies, confirming the efficacy of CPAP in treating severe OSA and CSA. While high-flow oxygen therapy has not been validated in this patient cohort, it may offer a potential solution for select patients, particularly the elderly and those with low compliance. Conventional oxygen therapy, however, is limited to cases of isolated nocturnal hypoxemia or mild central sleep apnea.

PMID:40217656 | DOI:10.3390/jcm14072205

Sci Rep. 2025 Apr 11;15(1):12442. doi: 10.1038/s41598-025-95307-0.

ABSTRACT

Diffuse pulmonary ossification (DiPO) is characterised by widespread ectopic bone formation in the lungs. Idiopathic DiPO (I-DiPO) poses significant diagnostic challenges and its ossification mechanism remains unclear. Cicatricial organising pneumonia (CiOP) lesions form fibrous nodules without damaging lung structure. We investigated the histopathological features of I-DiPO, focusing on the surrounding fibrosis, and compared them with those of secondary DiPO (S-DiPO). An analysis was conducted using data from a nationwide DiPO survey in Japan. The dataset included clinical, radiological, and histopathological data of patients with suspected I-DiPO. The specific patterns of ossification and fibrotic findings such as CiOP, organising pneumonia (OP), and subpleural fibrosis were identified. Eighteen and seven patients were classified as having I-DiPO and S-DiPO, respectively. I-DiPO affects younger patients, progresses slowly, commonly occurs in the lower lungs, and has a lower mortality rate. S-DiPO affects older patients, presents with widespread lung lesions, and has a higher mortality rate. CiOP lesions were found in direct continuity with or near ossified lesions in 61.1% and 71.4% of patients with I-DiPO and S-DiPO, respectively. OP, CiOP, and ossified lesions often observed in the same locations in S-DiPO. DiPO has a unique pathogenesis, with an ossification transition occurring via the CiOP lesions. These findings provide valuable insights for future diagnostic approaches and management strategies for this condition.

PMID:40216850 | DOI:10.1038/s41598-025-95307-0

Cell Death Dis. 2025 Apr 11;16(1):278. doi: 10.1038/s41419-025-07573-5.

ABSTRACT

Idiopathic pulmonary fibrosis has a poor prognosis, with existing medications only partially alleviating symptoms, highlighting the urgent need for new therapeutic approaches. The dysregulations of Rho GTPases/ROCK are related with various diseases, including fibrosis. Nevertheless, the development of drugs for pulmonary fibrosis treatment has predominantly concentrated on ROCK inhibitors. Small GTPases have been historically recognized as "undruggable". Here, we explore a novel Rho GEFs inhibitor GL-V9, and find that GL-V9 alleviates bleomycin-induced pulmonary fibrosis in mice by inhibiting myofibroblast activation and reprogramming profibrotic macrophages. Distinct from the mechanisms of the first-line drug Nintedanib, GL-V9 binds to the DH/PH domain of Rho GEFs and block the activation of Rho GTPase signaling. This action subsequently suppresses myofibroblast activation by interfering with Rho GTPase-dependent cytoskeletal reorganization and the activity of MRTF and YAP, and inhibits M2 macrophage polarization by modulating RhoA/STAT3 activity. The discovery of new regulatory mechanisms of GL-V9 suggests that targeting Rho GEFs represents a potent strategy for pulmonary fibrosis treatment.

PMID:40216763 | DOI:10.1038/s41419-025-07573-5

Cells. 2025 Apr 3;14(7):536. doi: 10.3390/cells14070536.

ABSTRACT

Fibrosing disorders including idiopathic pulmonary fibrosis (IPF) are progressive irreversible diseases, often with poor prognoses, characterized by the accumulation of excessive scar tissue and extracellular matrix. Translational regulation has emerged as a critical aspect of gene expression control, and the dysregulation of key effectors is associated with disease pathogenesis. This review examines the current literature on translational regulators in IPF, focusing on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and RNA transcript modifications including alternative polyadenylation and chemical modification. Some of these translational regulators potentiate fibrosis, and some of the regulators inhibit fibrosis. In IPF, some of the profibrotic regulators are upregulated, and some of the antifibrotic regulators are downregulated. Correcting these defects in IPF-associated translational regulators could be an intriguing avenue for therapeutics.

PMID:40214489 | DOI:10.3390/cells14070536

Cells. 2025 Mar 26;14(7):497. doi: 10.3390/cells14070497.

ABSTRACT

This paper investigates the ability of our selective small molecule TG2 inhibitor 1-155 in reducing fibrosis in a bleomycin-induced pulmonary fibrosis mouse model. Formulated as a fine stable suspension, 1-155 was delivered intranasally (IN) at 3 mg/kg via IN delivery once daily. It significantly inhibited collagen deposition in the lungs in the bleomycin-challenged mice. Compared to its vehicle control treatment, a significant reduction in a key myofibroblast marker α smooth muscle actin and TG2 was also detected in the 1-155-treated animals. Most importantly, 1-155 treatment significantly improved several key lung function parameters, such as cord compliance, vital capacity, and dynamic compliance, which are comparable to that found for the positive control nintedanib at a much higher dosage of 60 mg/kg twice daily via oral delivery. The 1-155-treated mice showed a trend in improvement of average body weight. For the first time, our study demonstrates the effectiveness of a selective small molecule TG2 inhibitor in reducing pulmonary fibrosis in a pre-clinical model. Importantly, we were able to correlate this effect of 1-155 with the improvement of animal lung function showing the potential of the use of TG2 inhibitors as a therapeutic treatment for fibrotic lung conditions like IPF.

PMID:40214451 | DOI:10.3390/cells14070497

Front Genet. 2025 Mar 27;16:1556495. doi: 10.3389/fgene.2025.1556495. eCollection 2025.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease characterized by unknown etiology and limited therapeutic options. Recent studies implicate exosomal non-coding RNAs (ncRNAs) as crucial regulators in IPF. These ncRNAs, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are involved in cellular processes through various mechanisms of selective packaging, intercellular communication, and signaling pathway integration. LncRNAs such as LINC00470 and PVT1 exhibit pro-fibrotic effects, while others like lnc-DC and THRIL show inhibitory roles; some, including UCA1 and MALAT1, demonstrate bidirectional regulation. In miRNAs, pro-fibrotic agents (e.g., miR-486, miR-223) contrast with inhibitory miRNAs (e.g., miR-34a, miR-126), while miR-21 and miR-155 display dual functions. Similarly, circRNAs such as circ_0000479 and circ_0026344 promote fibrosis, whereas circ_0000072 and circ_0000410 act as inhibitors, with certain circRNAs (e.g., circ_002178 and circ_0001246) exhibiting complex regulatory effects. Exosomal ncRNAs modulate key pathways, including TGF-β and Wnt/β-catenin, influencing IPF progression. Despite their potential, challenges remain in exosome isolation, functional characterization of ncRNAs, and clinical translation. Addressing these barriers through innovative research strategies is essential to leverage exosomal ncRNAs in the management and treatment of IPF. This review comprehensively examines the roles of exosomal ncRNAs in IPF, elucidates their mechanisms and pathway interactions, and discusses future perspectives to enhance understanding and therapeutic strategies for this disease.

PMID:40212286 | PMC:PMC11983508 | DOI:10.3389/fgene.2025.1556495

Ann Biomed Eng. 2025 Apr 10. doi: 10.1007/s10439-025-03729-8. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a life-threatening, progressive lung disease with limited therapeutic options, often resulting in poor patient outcomes. Current treatments, such as Nintedanib (NTB) and Pirfenidone (PFD), require frequent administration, leading to adverse effects and low patient adherence. The purpose of this study was to investigate a sustained-release drug delivery system utilizing microparticles (MPs) composed of insoluble beta-cyclodextrin (β-CD) polymers to enhance the bioavailability and extend the release of NTB and PFD.

METHODS: A multidisciplinary approach, including in silico modeling, in vitro assays, and in vivo studies, was employed to assess the efficacy of β-CD-polymer MPs as drug carriers.

RESULTS: Molecular docking simulations and surface plasmon resonance studies demonstrated a stronger binding affinity of NTB to β-CD-polymer MPs compared to PFD, suggesting an extended delivery profile for NTB over PFD. Pharmacokinetic analysis in healthy mice confirmed sustained-release profiles for both drugs, with NTB maintaining therapeutic plasma concentrations for over 70 h. In a bleomycin-induced IPF mouse model, NTB-loaded β-CD-polymer MPs significantly reduced pro-inflammatory markers and required fewer injections than the standard daily NTB regimen.

CONCLUSION: These findings indicate that β-CD-polymer MPs may serve as a promising platform for reducing dosing frequency of NTB and enhancing therapeutic outcomes in the treatment of IPF.

PMID:40210794 | DOI:10.1007/s10439-025-03729-8

Chest. 2025 Apr;167(4):931-932. doi: 10.1016/j.chest.2024.12.009.

NO ABSTRACT

PMID:40210309 | DOI:10.1016/j.chest.2024.12.009

Chest. 2025 Apr 8:S0012-3692(25)00422-2. doi: 10.1016/j.chest.2025.04.003. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are chronic fibrosing interstitial lung diseases associated with irreversible loss of lung function and early mortality. Admilparant (BMS-986278) is an oral lysophosphatidic acid receptor 1 (LPA1) antagonist under development for treatment of IPF and PPF.

RESEARCH QUESTION: How does admilparant affect time to disease progression in patients with IPF or PPF?

STUDY DESIGN AND METHODS: In a phase 2, randomized, double-blind, placebo-controlled study, parallel cohorts of patients with IPF or PPF were randomized separately 1:1:1 to receive 30-mg admilparant, 60-mg admilparant, or placebo twice daily for 26 weeks; background antifibrotics were allowed. The effect of admilparant vs placebo on time to disease progression was assessed post hoc. Disease progression was defined as a composite of relative decline of ≥10% in percentage of predicted forced vital capacity (ppFVC), acute exacerbation, all-cause hospitalization, and all-cause mortality. Subgroup analyses were performed based on median ppFVC at baseline. A Kaplan-Meier product-limit approach assessed time to first event of disease progression over 26 weeks.

RESULTS: In total, 255 patients with IPF and 114 patients with PPF were included. Median ppFVC at baseline was 77.3% and 64.7% in the IPF and PPF cohorts, respectively. Treatment with 60-mg admilparant delayed time to disease progression over 26 weeks compared with placebo in both cohorts of patients (IPF: hazard ratio, 0.54 [95% CI, 0.31-0.95]; PPF: hazard ratio, 0.41 [95% CI, 0.18-0.90]). A similar trend was observed in the subgroup analysis of patients with ppFVC at baseline either below or above the median value. In both cohorts, the most frequent first event was relative decline of ≥10% in ppFVC; no deaths were reported as first progression events.

INTERPRETATION: These findings support further evaluation of admilparant as a therapeutic option for patients with IPF or PPF in phase 3 trials.

PMID:40210090 | DOI:10.1016/j.chest.2025.04.003

Am J Respir Crit Care Med. 2025 Apr 10. doi: 10.1164/rccm.202502-0465ED. Online ahead of print.

NO ABSTRACT

PMID:40208255 | DOI:10.1164/rccm.202502-0465ED

Am J Respir Crit Care Med. 2025 Apr 10. doi: 10.1164/rccm.202407-1506OC. Online ahead of print.

ABSTRACT

RATIONALE: While idiopathic pulmonary fibrosis (IPF) has been widely studied, progressive non-IPF interstitial lung disease (ILD) remains poorly understood.

OBJECTIVE: To identify and validate proteomic biomarkers of non-IPF ILD survival.

METHODS: High-throughput proteomic data were generated using plasma collected as part of prospective registries at the Universities of California and Texas (discovery cohort, n=676) and PRECISIONS multi-omic study (validation cohort, n=616). Proteins associated with three-year transplant-free survival (TFS) were identified using multivariable Cox proportional hazards regression, and those associated with TFS after adjustment for false discovery were advanced for validation cohort testing. Pathway analysis was performed to identify molecular pathways unique to non-IPF ILD and shared with IPF.

MAIN RESULTS: Of 2925 proteins tested in the discovery cohort, 73 were associated with TFS, with 44 showing sustained TFS association in the validation cohort. The top TFS-associated proteins were amphiregulin (HR 2.51, 95% CI 2.07-3.04), integrin subunit beta 6 (HR 2.46; 95% CI 1.95-3.10) and keratin 19 (HR 1.70, 95% CI 1.47-1.98). All but one validated biomarkers showed consistent TFS association across non-IPF ILD subtypes. Pathway analysis identified several molecular pathways shared with IPF, along with three pathways unique to non-IPF ILD.

CONCLUSIONS: We identified and validated novel prognostic protein biomarkers in non-IPF ILD, most of which showed consistent association across non-IPF ILD subtypes. While most biomarkers and molecular pathways identified were previously linked to IPF, several were unique to non-IPF ILD, suggesting that unique biology may contribute to progressive non-IPF ILD.

PMID:40208180 | DOI:10.1164/rccm.202407-1506OC

Pathologica. 2025 Feb;117(1):3-9. doi: 10.32074/1591-951X-1123.

NO ABSTRACT

PMID:40205925 | DOI:10.32074/1591-951X-1123

Respir Res. 2025 Apr 9;26(1):128. doi: 10.1186/s12931-025-03201-0.

ABSTRACT

BACKGROUND: Cellular senescence is one of the key steps in the progression of pulmonary fibrosis, and the senescence of type II alveolar epithelial cells (AEC IIs) may potentially accelerate the progression of pulmonary fibrosis. However, the molecular mechanisms underlying cellular senescence in pulmonary fibrosis remain unclear.

METHODS: The researchers first conducted in vitro experiments to investigate whether AEC IIs cultured on high matrix stiffness would lead to cellular senescence. Next, samples from mouse pulmonary fibrosis models and clinical idiopathic pulmonary fibrosis (IPF) patients were tested to observe extracellular matrix deposition, lamin A/C levels, and cellular senescence status in lung tissue. Construct lamin A/C knockdown and overexpression systems separately in AEC IIs, and observe whether changes in lamin A/C levels lead to cellular senescence. Further explore the degradation mechanism of lamin A/C using protein degradation inhibitors.

RESULTS: In vitro experiments have found that high matrix stiffness promotes senescence of AEC IIs. In a mouse model of pulmonary fibrosis, AEC IIs were found to exhibit significant cellular senescence on day 21. In clinical IPF samples, it was found that senescent cells expressed low levels of lamin A/C. In the lamin A/C SiRNA knockdown system, it was further confirmed that AEC IIs with low levels of lamin A/C are more prone to cellular senescence. Under high matrix stiffness, lamin A/C in AEC IIs is degraded through the autophagy lysosome pathway. The use of chloroquine can effectively alleviate cellular senescence.

CONCLUSIONS: High matrix stiffness degrades lamin A/C in pulmonary fibrosis through lysosomal degradation pathways, promoting AEC II senescence. Inhibition the degradation of lamin A/C could alleviate AEC II senescence.

PMID:40205454 | DOI:10.1186/s12931-025-03201-0

Arerugi. 2025;74(2):83-88. doi: 10.15036/arerugi.74.83.

ABSTRACT

A 74-year-old man was treated with nintedanib for idiopathic pulmonary fibrosis (IPF). Thirty-six days after starting to take nintedanib, he admitted to our hospital due to respiratory failure with ground-glass opacities and mediastinal emphysema on chest CT. Acute exacerbation of IPF was suspected. Because lung injury due to nintedanib was suspected, nintedanib was discontinued. Although he was treated with pulse corticosteroid therapy, interstitial pneumonia and mediastinal emphysema deteriorated. Despite continuing corticosteroid therapy, he died 21 days after admission due to respiratory failure. Subsequently drug lymphocyte stimulation test for nintedanib was found to be positive. We should pay attention to possibility of drug-induced lung injury caused by nintedanib.

PMID:40204485 | DOI:10.15036/arerugi.74.83

Heliyon. 2025 Mar 14;11(6):e42984. doi: 10.1016/j.heliyon.2025.e42984. eCollection 2025 Mar 20.

ABSTRACT

[This corrects the article DOI: 10.1016/j.heliyon.2023.e21538.].

PMID:40201525 | PMC:PMC11948527 | DOI:10.1016/j.heliyon.2025.e42984

Front Med (Lausanne). 2025 Mar 27;12:1589992. doi: 10.3389/fmed.2025.1589992. eCollection 2025.

NO ABSTRACT

PMID:40201325 | PMC:PMC11977388 | DOI:10.3389/fmed.2025.1589992

BMJ Case Rep. 2025 Apr 8;18(4):e265092. doi: 10.1136/bcr-2025-265092.

ABSTRACT

A subset of idiopathic pulmonary fibrosis cases has a familial component. Telomeric mutations, such as those in the Regulator of Telomere Elongation Helicase 1 (RTEL1) gene, have been associated with lung fibrosis and a minority of dyskeratosis congenita (DC) cases.We present the case of a A male in his 50s with pulmonary fibrosis, cryptogenic hepatic cirrhosis, chronic anaemia and thrombocytopenia, lacy skin hyperpigmentation, dystrophic nails and canities. Family history included pulmonary fibrosis in two brothers. Genetic testing identified a RTEL1 mutation (c.3730T>C, p.Cys1244Arg) in heterozygosity, linked to a few cases of pulmonary fibrosis and DC. This mutation was confirmed in one brother and two sons. The patient was started on pirfenidone and referred for respiratory rehabilitation, haematological and transplant evaluations.Recognising family history and extrapulmonary manifestations in familial pulmonary fibrosis can expedite diagnosis, treatment and genetic counselling. Early detection of DC allows timely management of bone marrow failure and malignancy screening.

PMID:40199602 | DOI:10.1136/bcr-2025-265092

bioRxiv [Preprint]. 2025 Mar 24:2025.03.21.644589. doi: 10.1101/2025.03.21.644589.

ABSTRACT

Pseudomonas aeruginosa (PA) causes severe respiratory infections utilizing multiple virulence functions. Our previous findings on PA quorum sensing (QS)-regulated small molecule, 2'-aminoacetophenone (2-AA), secreted by the bacteria in infected tissues, revealed its effect on immune and metabolic functions favouring a long-term presence of PA in the host. However, studies on 2-AA's specific effects on bronchial-airway epithelium and pulmonary endothelium remain elusive. To evaluate 2AA's spatiotemporal changes in the human airway, considering endothelial cells as the first point of contact when the route of lung infection is hematogenic, we utilized the microfluidic airway-on-chip lined by polarized human bronchial-airway epithelium and pulmonary endothelium. Using this platform, we performed RNA-sequencing to analyse responses of 2-AA-treated primary human pulmonary microvascular endothelium (HPMEC) and adjacent primary normal human bronchial epithelial (NHBE) cells from healthy female donors and potential cross-talk between these cells. Analyses unveiled specific signaling and biosynthesis pathways to be differentially regulated by 2-AA in epithelial cells, including HIF-1 and pyrimidine signaling, glycosaminoglycan, and glycosphingolipid biosynthesis, while in endothelial cells were fatty acid metabolism, phosphatidylinositol and estrogen receptor signaling, and proinflammatory signaling pathways. Significant overlap in both cell types in response to 2-AA was found in genes implicated in immune response and cellular functions. In contrast, we found that genes related to barrier permeability, cholesterol metabolism, and oxidative phosphorylation were differentially regulated upon exposure to 2-AA in the cell types studied. Murine in-vivo and additional in vitro cell culture studies confirmed cholesterol accumulation in epithelial cells. Results also revealed specific biomarkers associated with cystic fibrosis and idiopathic pulmonary fibrosis to be modulated by 2-AA in both cell types, with the cystic fibrosis transmembrane regulator expression to be affected only in endothelial cells. The 2-AA-mediated effects on healthy epithelial and endothelial primary cells within a microphysiological dynamic environment mimicking the human lung airway enhance our understanding of this QS signaling molecule. This study provides novel insights into their functions and potential interactions, paving the way for innovative, cell-specific therapeutic strategies to combat PA lung infections.

PMID:40196568 | PMC:PMC11974707 | DOI:10.1101/2025.03.21.644589

J Pharm Biomed Anal. 2025 Apr 3;262:116868. doi: 10.1016/j.jpba.2025.116868. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a high-mortality chronic lung disease, and currently existing medications have limited therapeutic efficacy with noticeable adverse effects, urgently necessitating the exploration of more effective and safer treatment options. Our preliminary studies have demonstrated that the leech extract group with molecular weight greater than 10 kDa (>10 kDa group) exhibited superior anti-idiopathic pulmonary fibrosis efficacy. To trace the active components of > 10 kDa group, it was separated by gel electrophoresis and analyzed by Nano LC-MS/MS. To further analyze the effects of these active components on the regulation of metabolic pathways in fibrotic lung tissue, the metabolites of lung tissue were analyzed by UPLC/MS after administration of > 10 kDa group in bleomycin-induced pulmonary fibrosis (BML-induced PF) mice for 28 days at a 0.179 mg/g per day. A total of 17 proteins were identified in > 10 kDa group and 46 endogenous metabolites were identified in lung tissue, among which 18 significantly differential metabolites were screened as potential metabolomics biomarkers. Metabolic pathway analysis demonstrated that these identified differential metabolites mainly involved biosynthesis of unsaturated fatty acids, phenylalanine-tyrosine and tryptophan biosynthesis and tryptophan metabolism signaling pathway, indicating that the active components of > 10 kDa group mainly regulated the metabolic disorders of lung tissue in BLM-induced mice by up-regulating the biosynthesis of unsaturated fatty acids, down-regulating phenylalanine-tyrosine and tryptophan biosynthesis, and adjusting tryptophan metabolism signaling pathway.

PMID:40194473 | DOI:10.1016/j.jpba.2025.116868