J Mol Model. 2025 Mar 24;31(4):124. doi: 10.1007/s00894-025-06338-3.

ABSTRACT

CONTEXT: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by very limited treatment options and significant side effects from existing therapies, highlighting the urgent need for more effective drug-like molecules. Transforming growth factor-beta receptor 1 (TGF-βR1) is a key player in the pathogenesis of IPF and represents a critical target for therapeutic intervention. In this study, the potential of plant-derived flavonoid and coumarin compounds as novel TGF-βR1 inhibitors was explored. A total of 1206 flavonoid and coumarin derivatives were investigated through a series of computational approaches, including drug-like filtering, virtual screening, molecular docking, 200-ns molecular dynamics (MD) simulations in triplicate, maximum common substructure (MCS) analysis, and absorption-distribution-metabolism-excretion-toxicity (ADMET) profiling. 2',3',4'-trihydroxyflavone and dicoumarol emerged as promising plant-based hit candidates, exhibiting comparable docking scores, MD-based structural stability, and more negative MM/PBSA binding free energy relative to the co-crystallized inhibitor, while surpassing pirfenidone in these parameters and demonstrating superior pharmacological properties. In light of the findings from this study, 2',3',4'-trihydroxyflavone and dicoumarol could be considered novel TGF-βR1 inhibitors for IPF treatment, and it is recommended that their structural optimization be pursued through in vitro binding assays and in vivo animal studies.

METHODS: The initial dataset of 1206 flavonoid and coumarin derivatives was filtered for drug-likeness using Lipinski's Rule of Five in the ChemMaster-Pro 1.2 program, resulting in 161 potential candidates. These compounds were then subjected to virtual screening against the TGF-βR1 kinase domain (PDB ID: 6B8Y) using AutoDock Vina 1.2.5, identifying the top three hit compounds-dicoumarol, 2',3',4'-trihydroxyflavone, and 2',3'-dihydroxyflavone. These hits underwent further exhaustive molecular docking for refinement of docking poses, followed by 200-ns MD simulations in triplicate using the AMBER03 force field in GROMACS. Subsequently, the binding free energies were calculated using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. MCS analysis was conducted to determine shared structural features among the top three hits, while ADMET properties were predicted using Deep-PK, a deep learning-based platform. Finally, the ligand-protein interactions were further visualized, analyzed, and rendered using ChimeraX, Discovery Studio Visualizer, and Visual Molecular Dynamics (VMD) program.

PMID:40126695 | DOI:10.1007/s00894-025-06338-3

Am J Respir Cell Mol Biol. 2025 Mar 24. doi: 10.1165/rcmb.2024-0342OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder without curative therapies, underscoring the critical unmet need for identification of novel therapeutics. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand that contributes to the severity of radiation-induced lung fibrosis and NASH-associated hepatic fibrosis. This study investigates eNAMPT as a druggable target in human and preclinical IPF utilizing the eNAMPT-neutralizing ALT-100 monoclonal antibody (mAb). Blood, PBMCs, and lung tissues from IPF patients and from an experimental bleomycin-induced lung fibrosis model in C57Bl6 mice were analyzed. Biochemical and histologic measurements, as well as gene expression through bulk and single-cell RNA sequencing of human PBMCs and murine lung tissues were performed. Human studies revealed NAMPT expression to be significantly elevated in plasma, lung tissues, and in PBMCs from IPF subjects, correlating with disease severity and inversely associated with IPF survival. Bleomycin-exposed mice exhibited increased inflammatory indices associated with lung fibrosis development (including NAMPT levels), as well as physiologic lung stiffening, and TGFβ pathway-related protein and gene expression with each indice significantly mitigated in mice receiving ALT-100 mAb. scRNAseq studies demonstrated the ALT-100 mAb to reverse bleomycin-induced dramatic expansion of alveolar type 2 epithelium (AT2) and indiction of endothelial- and epithelial cell-to-mesenchymal/myofibroblast transitions (EndMT, EMT). These finding support the fundamental involvement of eNAMPT/TLR4 signaling pathway in lung fibrosis pathobiology with eNAMPT neutralization a viable therapeutic strategy to directly address the unmet need for novel IPF treatments.

PMID:40126452 | DOI:10.1165/rcmb.2024-0342OC

Ther Deliv. 2025 Mar 24:1-14. doi: 10.1080/20415990.2025.2478803. Online ahead of print.

ABSTRACT

AIMS: Diltiazem (DIL), a calcium channel blocker, has demonstrated potential ininhibiting fibrosis-related processes, including TGF-β activation, collagen production, and epithelial-mesenchymal transition, making it a promising candidate for idiopathic pulmonary fibrosis (IPF). This study evaluates the anti-fibrotic efficacy of DIL-loaded chitosan (DIL-CHT) and trimethyl chitosan (DIL-TMC) nanoparticles through molecular and experimental approaches.

METHODS: DIL-CHT and DIL-TMC nanoformulations were developed and analyzed particle size, ζ-potential, entrapment efficiency, and in vitro release. Antifibrotic efficacy in bleomycin (BLM)-induced IPF rat model, was tested at subtherapeutic doses (3 mg/kg/day, i.t.) and DIL alone (10 mg/kg/day, p.o.). DFT (B3LYP/6-31 G**) optimization and molecular docking were conducted to assess electronic properties and interactions among CHT, TMC, and DIL.

RESULTS: DIL-TMC and DIL-CHT nanoparticles were 175.6 nm and 267.8 nm, with entrapment efficiencies of 81.72% and 66.0%, respectively; TMC showed a superior 24-hour sustained release. TMC's larger HOMO-LUMO gap (ΔE = -0.260 eV vs. -0.253 eV for CHT) suggests greater stability, supporting its enhanced interaction with DIL. TMC nanoparticles significantly reduced BLM-induced IPF symptoms, i.e. BLM induced increased lung index, hydroxyproline accumulation, oxidative stress in lung tissue, and blood pressure.

CONCLUSIONS: These findings indicate the strong therapeutic potential of DIL-TMC for IPF with minimal cardiovascular side effects.

PMID:40125984 | DOI:10.1080/20415990.2025.2478803

Physiol Rev. 2025 Mar 24. doi: 10.1152/physrev.00032.2024. Online ahead of print.

ABSTRACT

Nanosized extracellular vesicles (EVs) are released by all cells to convey cell-to-cell communication. EVs, including exosomes and microvesicles, carry an array of bioactive molecules, such as proteins and RNAs, encapsulated by a membrane lipid bilayer. Epithelial cells, endothelial cells, and various immune cells in the lung contribute to the pool of EVs in the lung microenvironment and carry molecules reflecting their cellular origin. EVs can maintain lung health by regulating immune responses, inducing tissue repair, and maintaining lung homeostasis. They can be detected in lung tissues and biofluids such as bronchoalveolar lavage fluid and blood, offering information about disease processes and can function as disease biomarkers. Here, we discuss the role of EVs in lung homeostasis and pulmonary diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, and lung injury. The mechanistic involvement of EVs in pathogenesis and their potential as disease biomarkers are discussed. Lastly, the pulmonary field benefits from EVs as clinical therapeutics in severe pulmonary inflammatory disease, as EVs from mesenchymal stem cells attenuate severe respiratory inflammation in multiple clinical trials. Further, EVs can be engineered to carry therapeutic molecules for enhanced and broadened therapeutic opportunities, such as the anti-inflammatory molecule CD24. Finally, we discuss the emerging opportunity of using different types of EVs for treating severe respiratory conditions.

PMID:40125970 | DOI:10.1152/physrev.00032.2024

Fibrosis (Hong Kong). 2025;3(1):10004. doi: 10.70322/fibrosis.2025.10004. Epub 2025 Feb 18.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is marked by progressive alveolar destruction, impaired tissue regeneration, and relentless fibrogenesis, culminating in respiratory failure and death. A diverse array of resident and non-resident cells within the lung contribute to disease pathogenesis. Notably, immune cells, both resident and recruited, respond to cues from sites of lung injury by undergoing phenotypic transitions and producing a wide range of mediators that influence, initiate, or dictate the function, or dysfunction, of key effector cells in IPF pathology, such as alveolar epithelial cells, lung fibroblasts, and capillary endothelial cells. The role of the immune system in IPF has undergone an interesting evolution, oscillating from initial enthusiasm to skepticism, and now to a renewed focus. This shift reflects both the past failures of immune-targeting therapies for IPF and the unprecedented insights into immune cell heterogeneity provided by emerging technologies. In this article, we review the historical evolution of perspectives on the immune system's role in IPF pathogenesis and examine the lessons learned from previous therapeutic failures targeting immune responses. We discuss the major immune cell types implicated in IPF progression, highlighting their phenotypic transitions and mechanisms of action. Finally, we identify key knowledge gaps and propose future directions for research on the immune system in IPF.

PMID:40124525 | PMC:PMC11928166 | DOI:10.70322/fibrosis.2025.10004

Anal Chem. 2025 Mar 23. doi: 10.1021/acs.analchem.4c06786. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible fatal disease, the prevalence of which has been increasing in recent years. Nonradiographic and noninvasive early diagnosis of pulmonary fibrosis could improve prognosis but is a formidable challenge. As one of the fundamental microenvironmental parameters, viscosity is relevant to various pathological states, such as acute inflammation. Nevertheless, the potential biological roles of viscosity during the IPF process have been relatively underexplored. To address this issue, herein, we developed a new viscosity-responsive probe (JZ-2), which displayed high sensitivity and selectivity for viscosity, as well as excellent characteristics for targeting mitochondria. JZ-2 was successfully applied to map the changes in mitochondrial viscosity in cells caused by various stimuli, such as nystatin and lipopolysaccharide. Besides, JZ-2 was capable of differentiating cancer cells from normal cells and even tissues. More importantly, JZ-2 has been demonstrated to be sufficiently sensitive for tumor detection and early identification of IPF in vivo, revealing a significant increase in the viscosity of lung fibrosis tissues. Thus, JZ-2 is expected to be a swift and reliable diagnostic modality for the prediction of IPF progression in clinical settings.

PMID:40123047 | DOI:10.1021/acs.analchem.4c06786

Sci Rep. 2025 Mar 23;15(1):10009. doi: 10.1038/s41598-025-94801-9.

ABSTRACT

The swift transmission rate and unfavorable prognosis associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have prompted the pursuit of more effective therapeutic interventions. Azithromycin (AZM) has garnered significant attention for its distinctive pharmacological mechanisms in the treatment of SARS-CoV-2. This study aims to elucidate the biological rationale for employing AZM in patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) who are infected with SARS-CoV-2. Genetic data about COVID-19, COPD, and IPF were independently obtained from the GeneCards database. And 40 drug targets about AZM were retrieved from the STITCH database. The analysis revealed that 311 DEGs were common among COPD, IPF, and COVID-19, and we further found eight genes that interacted with AZM targets. We conducted an analysis of hub genes and their corresponding signaling pathways in these patient cohorts. Additionally, we explored the inhibitory effects of AZM on these hub genes. AZM demonstrated a significant inhibitory effect on eight key genes, except for AR and IL-17 A. These findings suggest that AZM may serve as a promising therapeutic agent for patients with COPD and IPF and SARS-CoV-2 infection.

PMID:40122903 | DOI:10.1038/s41598-025-94801-9

Respirology. 2025 Mar 23. doi: 10.1111/resp.70030. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Real-world data on lung function course of patients with progressive pulmonary fibrosis (PPF) treated with anti-fibrotic medication are limited. We evaluated forced vital capacity (FVC) decline in patients with PPF and idiopathic pulmonary fibrosis (IPF) who started anti-fibrotic treatment.

METHODS: This was a nationwide multi-centre registry study in 16 hospitals throughout the Netherlands. Patients treated with anti-fibrotic medication, with at least two in-hospital pulmonary function tests before and after the initiation of anti-fibrotic treatment, were included. Linear mixed-effects modelling was used to analyse lung function trajectories 1 year before and after the start of anti-fibrotic treatment.

RESULTS: Data from 538 patients (n = 142 with PPF, n = 396 with IPF) were analysed. In PPF, the mean annualised FVC decline was 412 mL (95% confidence interval [CI]: 308-517 mL) before the initiation of anti-fibrotic treatment, and 18 mL (95% CI: 9-124 mL) in the first year after. The corresponding declines for IPF were 158 mL (95% CI: 78-239 mL) and 38 mL (95% CI: 24-101 mL). In both groups, treatment significantly slowed down FVC decline, although the change was larger in the PPF group (p = 0.0006). In the first year after treatment initiation, 28.0% of patients with PPF and 27.4% with IPF had disease progression.

CONCLUSION: The FVC decline significantly slowed after the initiation of treatment for both IPF and PPF. Nevertheless, a significant proportion of patients exhibited disease progression, despite the start of anti-fibrotic treatment. Early identification of these patients is crucial for treatment adaptations and inclusion in clinical trials.

PMID:40122143 | DOI:10.1111/resp.70030

Respir Res. 2025 Mar 22;26(1):111. doi: 10.1186/s12931-025-03187-9.

ABSTRACT

The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines-Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors-Ccr2 and Ccr5-in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines-TNF-α; IL-6 and chemokine receptor-CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.

PMID:40121473 | DOI:10.1186/s12931-025-03187-9

BMJ Open Respir Res. 2025 Mar 22;12(1):e002327. doi: 10.1136/bmjresp-2024-002327.

ABSTRACT

INTRODUCTION: Breathlessness is common and impairs the quality of life of people with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic interstitial lung diseases (ILD). We report the findings of a multicentre, fast-track (wait-list), mixed-methods, randomised controlled, feasibility study of a complex breathlessness intervention in breathless IPF and non-IPF fibrotic ILD patients.

METHODS: Breathless IPF and non-IPF fibrotic ILD patients were randomised to receive the intervention within 1 week (fast-track) or after 8 weeks (wait-list). The intervention comprised two face-to-face and one telephone appointment during a 3-week period covering breathing control, handheld fan-use, pacing and breathlessness management techniques, and techniques to manage anxiety. Feasibility and clinical outcomes were assessed to inform progression to, and optimal design for, a definitive trial. A qualitative substudy explored barriers and facilitators to trial and intervention delivery.

RESULTS: 47 patients (M:F 38:9, mean (SD) age 73.9 (7.2)) were randomised with a recruitment rate of 2.5 participants per month across three sites. The adjusted mean differences (95% CI) for key clinical outcomes at 4 weeks post randomisation were as follows: Chronic Respiratory Questionnaire breathlessness mastery domain (0.45 (-0.07, 0.97)); and numerical rating scales for 'worst' (-0.93 (-1.95, 0.10)), 'best' (-0.19 (-1.38, 1.00)), 'distress caused by' (-1.84 (-3.29, -0.39)) and 'ability to cope with' (0.71 (-0.57, 1.99)) breathlessness within the past 24 hours. The qualitative substudy confirmed intervention acceptability and informed feasibility and acceptability of study outcome measures.

CONCLUSION: A definitive trial of a complex breathlessness intervention in patients with IPF and non-IPF fibrotic ILD is feasible with preliminary data supporting intervention effectiveness.

TRIAL REGISTRATION NUMBER: ISRCTN13784514.

PMID:40121019 | DOI:10.1136/bmjresp-2024-002327

Aging Clin Exp Res. 2025 Mar 22;37(1):101. doi: 10.1007/s40520-025-03009-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is more likely to occur in the elderly population, and these patients often become depressed. It has been recognized that psychological disorders are not conducive to the control of many diseases. Thus, this study aims to determine whether alleviating depression can delay the progression of IPF and frailty in elderly patients with IPF.

METHODS: IPF patients over 60 years old were included in the study. None had a prior history of psychological disorders. All developed depression after being diagnosed with IPF. During the 12-month follow-up, some patients received anti-depression interventions and the rest didn't. Depression, IPF, frailty and peripheral inflammation at baseline and after follow-up were evaluated by indicators and scales such as BDI-II, FVC %pred, 6MWT, mMRC, CFS, TFI, SGRQ, K-BILD, IL-6, and TNF-α. Multivariate logistic regression was employed for data analysis.

RESULTS: There were 213 elderly patients with IPF. Among the 89 patients who received anti-depression interventions, the above-mentioned indicators and scales did not deteriorate during the follow-up period (P > 0.05). Among the remaining 124 patients, the FVC %pred, and 6MWT levels decreased, and the mMRC grade, CFS, TFI, SGRQ and K-BILD scores, and peripheral IL-6 and TNF-α levels increased during the follow-up period (P < 0.05).

DISCUSSION: Compared with non-intervened IPF patients, those receiving anti-depression interventions seemed to maintain a certain stability in IPF, frailty, and peripheral inflammation over a period.

CONCLUSION: Improving depression may help delay the deterioration of patients' IPF and frailty at certain stages.

TRIAL REGISTRATION: Registration on UMIN-CTR.

REGISTRATION NUMBER: UMIN000057161. Date of registration: February 27th, 2025.

PMID:40120048 | DOI:10.1007/s40520-025-03009-4

Fam Cancer. 2025 Mar 22;24(2):31. doi: 10.1007/s10689-025-00455-x.

ABSTRACT

Telomere biology disorders (TBDs) are a group of genetic conditions characterized by defects in telomere maintenance leading to multisystemic organ involvement and a predisposition to hematologic malignancies. The management of patients with TBDs who develop acute myeloid leukemia (AML) presents a significant challenge due to their limited bone marrow reserve and non-hematopoietic organ dysfunction. We present the case of a 45-year-old patient with a previously unrecognized TBD who presented with AML. The patient's history of longstanding cytopenias, idiopathic avascular necrosis, and pulmonary fibrosis were suggestive of a TBD, which was confirmed through telomere length testing and the presence of a TERT variant. Due to his underlying TBD, he was treated with dose-reduced azacitidine and venetoclax, adapting the approach commonly employed in elderly, co-morbid AML patients ineligible for intensive chemotherapy. This resulted in a complete remission with incomplete count recovery that has persisted for greater than 12 months to date. Aside from prolonged myelosuppression, the patient tolerated the regimen well with minimal toxicity. To our knowledge, this is the first report of the successful utilization of azacitidine and venetoclax as an AML treatment modality in TBD patients and underscores the potential of this regimen as an effective non-intensive treatment strategy for high grade myeloid neoplasms arising in the context of inherited bone marrow failure syndromes.

PMID:40119960 | DOI:10.1007/s10689-025-00455-x

Environ Sci Technol. 2025 Mar 22. doi: 10.1021/acs.est.4c11275. Online ahead of print.

ABSTRACT

Gaseous pollutants such as CO, NO2, O3, and SO2 are linked to adverse clinical outcomes in patients with fibrotic interstitial lung diseases (fILDs), particularly idiopathic pulmonary fibrosis. However, the effect of various exposure estimation methods on these findings remains unclear. This study aims to evaluate three spatial approaches─nearest neighbor (NN), inverse distance weighting (IDW), and Kriging─for estimating gaseous pollutant exposures and to assess how these methods affect health outcome estimates in fILD patients. A 10-fold cross-validation showed that Kriging had the lowest prediction error compared to NN and IDW, with RMSE for CO = 0.43 ppm (11%), O3 = 5.9 ppb (14%), SO2 = 2.7 ppb (12%), and NO2 = 7.6 ppb (9%), respectively. Kriging also excelled over other methods across wide spatial and temporal ranges, showing the highest spatial R2 for CO and O3 and the highest temporal R2 for SO2 and NO2. In a large cohort of patients with fILD, higher levels of CO, SO2, and NO2 exposure were associated with lower pulmonary function. The magnitude of association and its precision were higher in SO2 and CO estimated by the Kriging method. This study underscores Kriging as a robust method for estimating gaseous pollutant levels and offers valuable insights for future epidemiological studies.

PMID:40119855 | DOI:10.1021/acs.est.4c11275

Adv Sci (Weinh). 2025 Mar 22:e2405434. doi: 10.1002/advs.202405434. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) remains an incurable form of interstitial lung disease with sub-optimal treatments that merely address adverse symptoms or slow fibrotic progression. Here, inhalable hsa-miR-30a-3p-loaded liposomes (miR-30a) for the treatment of bleomycin-induced pulmonary fibrosis in mice are presented. It was previously found that exosomes (Exo) derived from lung spheroid cells are therapeutic in multiple animal models of pulmonary fibrosis and are highly enriched for hsa-miR-30a-3p. The present study investigates this miRNA as a singular factor to treat IPF. Liposomes containing miR-30a mimic can be delivered to rodents through dry powder inhalation. Inhaled miR-30a and Exo consistently lead to improved pulmonary function across six consecutive pulmonary function tests and promote de-differentiation of profibrotic myofibroblasts. The heterogenous composure of Exo also promotes reparative alveolar type I and II cell remodeling and vascular wound healing through broad transforming growth factor-beta signaling downregulation, while miR-30a targets myofibroblast de-differentiation through CNPY2/PERK/DDIT3 signaling. Overall, inhaled miR-30a represses the epithelial-mesenchymal transition of myofibroblasts, providing fibrotic attenuation and subsequent improvements in pulmonary function.

PMID:40119620 | DOI:10.1002/advs.202405434

Cell Death Dis. 2025 Mar 21;16(1):196. doi: 10.1038/s41419-025-07522-2.

ABSTRACT

The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes the interconversion of active glucocorticoid (cortisol) and its intrinsically inert form (cortisone) in metabolic tissues. Although 11βHSD1 is considered a promising therapeutic target in metabolic disorders such as type 2 diabetes, obesity, and nonalcoholic steatohepatitis because of its hepatic functions, its roles in other tissues have received less attention. In this study, we show that the 11βHSD1-specific inhibitor J2H-1702 facilitates the reversion of endothelial-to-mesenchymal transition in multicellular lung spheroid models encapsulating the complex crosstalk among lung cancer cells, vascular endothelial cells, and macrophages. In vascular endothelial cells, J2H-1702 not only suppressed interleukin-1α (IL-1α) expression but also attenuated reactive oxygen species-induced DNA damage by upregulating heme oxygenase-1. Additionally, in macrophages, which are key regulators of fibrogenesis, inhibition of 11βHSD1 markedly reduced IL-1β expression, thereby modulating the pro-inflammatory phenotype of activated macrophages. In mouse models of pulmonary fibrosis, including a bleomycin-induced idiopathic model and a radiation-induced model, J2H-1702 alleviated pulmonary fibrosis and markedly improved the efficacy of nintedanib. Collectively, our data suggest that J2H-1702 holds promise as a clinical candidate for the treatment of pulmonary fibrosis associated with reactive oxygen species-induced DNA damage, endothelial-to-mesenchymal transition, and inflammatory responses.

PMID:40118823 | DOI:10.1038/s41419-025-07522-2

Clin Exp Immunol. 2025 Mar 21:uxaf019. doi: 10.1093/cei/uxaf019. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD.

METHODS: A murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of IL-1β, IL-6 and TNF-α were detected by ELISA. PFD was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of CitH3 and MPO in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot was utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NLRP3 inflammasome markers.

RESULTS: PFD treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. PFD intervention reduced NETs formation in vitro. PFD treatment significantly reduce NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD down-regulated EMT and NLRP3-related proteins in vivo. PFD treatment also notably reduced serum levels of IL-1β, IL-6 and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. PFD attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome.

CONCLUSION: PFD alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.

PMID:40117382 | DOI:10.1093/cei/uxaf019

J Family Med Prim Care. 2025 Feb;14(2):807-810. doi: 10.4103/jfmpc.jfmpc_642_24. Epub 2025 Feb 21.

ABSTRACT

IPF is a chronic lung disease that is characterized by progressive deterioration of pulmonary function associated with scarring of the lung interstitium, resulting in decreased vital capacity and lung compliance. The disease usually manifests in the sixth and seventh decades of life and incidence increases with advance in age and is more common in males.[1] Risk factors include hereditary factors, chronic viral infection, history of smoking, exposure to hazardous substances in the environment, acid reflux disease, etc. An inexplicable cough, low-grade fever, difficulty in breathing, loss of weight, and appetite are common presentations in patients with IPF. Respiratory examination shows bibasilar inspiratory crepitations. Here, we describe a unique case of ILD presented at an upper middle age of 45 years and so misdiagnosed as pulmonary tuberculosis which presented as a diagnostic and clinical challenge.

PMID:40115548 | PMC:PMC11922384 | DOI:10.4103/jfmpc.jfmpc_642_24

Thorax. 2025 Mar 20:thorax-2023-221063. doi: 10.1136/thorax-2023-221063. Online ahead of print.

ABSTRACT

BACKGROUND: Long-term oxygen therapy (LTOT) improves survival in patients with chronic severe resting hypoxaemia, but effects on hospitalisation are unknown. This study evaluated the potential impact of starting LTOT on acute exacerbation and hospital burden in patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and pulmonary hypertension (PH).

METHODS: Longitudinal analysis of consecutive patients in the population-based Swedish DISCOVERY cohort who started LTOT between 2000 and 2018 with a follow-up duration≥3 months. Total and hospitalised acute exacerbations of the underlying disease, all-cause hospitalisations, and all-cause outpatient visits were annualised and compared between the year before and after LTOT initiation for each disease cohort, and by hypercapnic status in patients with COPD.

RESULTS: Patients with COPD (n=10 134) had significant reduction in annualised rates of total and hospitalised acute exacerbations, as well as all-cause hospitalisations, following LTOT initiation, with increment in those with ILD (n=2507) and PH (n=850). All-cause outpatient visits increased across all cohorts following LTOT initiation. Similar findings were observed in patients with hypercapnic and non-hypercapnic COPD. Sensitivity analyses of patients with 12 months of follow-up showed reduced acute exacerbations and all-cause hospitalisations in the ILD and PH cohorts.

CONCLUSION: LTOT is associated with reduced rates of both total and hospitalised acute exacerbations and all-cause hospitalisations in patients with COPD, as well as patients with ILD and PH with 12 months of follow-up. There is increased all-cause outpatient visits in all disease groups following LTOT initiation.

PMID:40113248 | DOI:10.1136/thorax-2023-221063

Bioorg Chem. 2025 Mar 11;159:108360. doi: 10.1016/j.bioorg.2025.108360. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and fatal pulmonary disease. Owing to its complex pathogenesis and lack of effective treatment, patients have a short survival time after diagnosis. Although pirfenidone and nintedanib can mitigate declines in lung function, neither has stopped the progression of IPF nor significantly improved long-term survival in patients. HDAC6 inhibitors have been reported to inhibit TGF-β1-induced collagen expression to protect mice from pulmonary fibrosis, and this pharmacological mechanism has been supported by immunohistochemical studies of HDAC6 overexpression in IPF lung tissue. In this study, a series of novel derivatives were obtained based on the reported active compounds through the ring closure strategy in scaffold hopping theory. Compound W28 was selected from in vitro screening for better HDAC6 selectivity, and it was used for in-depth pharmacokinetic and pharmacodynamic studies. Detailed molecular docking studies, molecular dynamics (MD) simulations and the structure-activity relationship (SAR) discussion will contribute to guiding the design of new molecules. In further studies, the ability of W28 to inhibit the IPF phenotype was confirmed, and the corresponding pharmacological mechanism was also demonstrated. Moreover, the pharmacokinetic characteristics of W28 were also tested to guide pharmacodynamic studies in vivo, and the therapeutic effect of W28 on bleomycin-induced pulmonary fibrosis in mice was found to be satisfactory. The results reported in this paper may provide a reference for promoting the discovery of new selective HDAC6 inhibitors as drug molecules for the treatment of IPF.

PMID:40112668 | DOI:10.1016/j.bioorg.2025.108360

Adv Sci (Weinh). 2025 Mar 20:e2415007. doi: 10.1002/advs.202415007. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive fibroblast recruitment and persistent extracellular matrix deposition at sites of tissue injury, leading to severe morbidity and mortality. However, the precise mechanisms by which fibroblasts contribute to IPF pathogenesis remain poorly understood. The study reveals that Sema3E and its receptor Plexin D1 are significantly overexpressed in the lungs of IPF patients and bleomycin (BLM)-induced lung fibrotic mice. Elevated plasma levels of Sema3E in IPF patients are negatively correlated with lung function. Importantly, Sema3E in IPF lungs predominantly exists as the P61-Sema3E. The knockdown of Sema3E or Plexin D1 effectively inhibits fibroblast activation, proliferation, and migration. Mechanistically, Furin-mediated cleavage of P87-Sema3E into P61-Sema3E drives these pro-fibrotic activities, with P61-Sema3E-PlexinD1 axis promoting fibroblast activation, proliferation, and migration by affecting the phosphorylation of ErbB2, which subsequently activates the ErbB2 pathways. Additionally, Furin inhibition reduces fibroblast activity by decreasing P61-Sema3E production. In vivo, both whole-lung Sema3E knockdown and fibroblast-specific Sema3E knockout confer protection against BLM-induced lung fibrosis. These findings underscore the crucial role of the P61-Sema3E-Plexin D1 axis in IPF pathogenesis and suggest that targeting this pathway may hold promise for the development of novel therapeutic strategies for IPF treatment.

PMID:40112179 | DOI:10.1002/advs.202415007