BMJ Open. 2025 Feb 5;15(2):e088604. doi: 10.1136/bmjopen-2024-088604.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease frequently complicated by gastro-oesophageal reflux disease. Although several observational studies and a pilot study have investigated the role of proton pump inhibitors (PPIs) in IPF, their efficacy is unknown and there is much debate in international IPF guidelines on their use. We aim to undertake an adequately powered double-blind placebo-controlled randomised multicentre clinical trial to assess the change in forced vital capacity (FVC), cough and other important patient-reported outcomes, following 12-month therapy with PPIs in people with IPF.

METHODS AND ANALYSIS: A total of 298 patients with IPF diagnosed by a multidisciplinary team according to international guidelines who are not receiving PPIs will be enrolled. Patients are randomised equally to receive two capsules of lansoprazole or two placebo capsules, two times per day for 12 months. The primary outcome for the trial is change in FVC, measured at home, between the first week and last week of the study period. Secondary assessments include cough frequency (in a subgroup) measured using the VitaloJAK cough monitor, the King's Brief Interstitial Lung Disease questionnaire, the Raghu Scale for Pulmonary Fibrosis, Medical Research Council dyspnoea score, EQ-5D-5L, Leicester Cough Questionnaire, modified DeMeester reflux symptoms questionnaire and opportunistically captured routine lung function measurements. High-resolution CT scoring will be undertaken in a subgroup. The trial is designed to determine whether treating people with IPF with lansoprazole will reduce the reduction in FVC over a year. The COVID-19 pandemic required the study to be undertaken as a remote trial.

ETHICS AND DISSEMINATION: This study received ethical approval from the East of England Cambridgeshire and Hertfordshire Research Ethics Committee (reference 20/EE/0043; integrated research application system number 269050). Trial results will be published in a peer-reviewed journal upon completion.

TRIAL REGISTRATION NUMBER: ISRCTN13526307; ClinicalTrials.gov NCT04965298.

PMID:39909521 | DOI:10.1136/bmjopen-2024-088604

Eur Respir Rev. 2025 Feb 5;34(175):240080. doi: 10.1183/16000617.0080-2024. Print 2025 Jan.

ABSTRACT

Interstitial lung disease (ILD) is a clinical term that refers to a diverse group of non-neoplastic lung diseases. This group includes idiopathic and secondary pulmonary entities that are often associated with progressive pulmonary fibrosis. Currently, therapeutic approaches based on specific structural targeting of pulmonary fibrosis are limited to nintedanib and pirfenidone, which can only slow down disease progression leading to a lower mortality rate. Lung transplantation is currently the only available curative treatment, but it is associated with high perioperative mortality. The pulmonary vasculature plays a central role in physiological lung function, and vascular remodelling is considered a hallmark of the initiation and progression of pulmonary fibrosis. Different patterns of pulmonary fibrosis commonly exhibit detectable pathological features such as morphomolecular changes, including intussusceptive and sprouting angiogenesis, vascular morphometry, broncho-systemic anastomoses, and aberrant angiogenesis-related gene expression patterns. Dynamic cellular interactions within the fibrovascular interface, such as endothelial activation and endothelial-mesenchymal transition, are also observed. This review aims to summarise the current clinical, radiological and pathological diagnostic algorithm for different ILDs, including usual interstitial pneumonia/idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, alveolar fibroelastosis/pleuroparenchymal fibroelastosis, hypersensitivity pneumonitis, systemic sclerosis-related ILD and coronavirus disease 2019 injury. It emphasises an interdisciplinary clinicopathological perspective. Additionally, the review covers current therapeutic strategies and knowledge about associated vascular abnormalities.

PMID:39909504 | DOI:10.1183/16000617.0080-2024

Eur J Radiol. 2025 Jan 30;184:111961. doi: 10.1016/j.ejrad.2025.111961. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the reliability, validity and applicability of ILD-RADS among readers with different levels of experience.

METHODS: This prospective tri-center study included 159 patients with clinically diagnosed ILD who underwent high-resolution CT (HRCT). Two experienced thoracic radiologists, two general radiologists, and one pulmonologist independently evaluated the HRCT images blinded to the patient's clinical data and assigned ILD-RADS category for each patient. The Fleiss kappa test was employed to estimate the inter-reader agreement among all readers. Cohen's kappa test was applied to measure the pairwise inter-reader agreement. The multi-disciplinary team discussion (MDD) was used as a reference test to estimate the validity of ILD-RADS for diagnosing idiopathic pulmonary fibrosis (IPF). A 5-point Likert short survey was accomplished by the pulmonologists about the applicability of ILD-RADS in clinical practice.

RESULTS: The current study included 124 non-IPF and 35 IPF cases. Based on the radiologists, the ILD-RADS showed moderate inter-reader agreement (K = 0.515, P < 0.001) while being fair after the inclusion of the pulmonologist's input (K = 0.333, P < 0.001). The agreement was substantial among thoracic radiologists (K = 0.716, p < 0.001) and moderate among general radiologists (K = 0.461, p < 0.001). ILD-RADS ≤ 2 was the optimal cut-off for predicting IPF, with an accuracy ranging from 62.84 % to 80.54 %. Seventy-five percent of pulmonologists rated ILD-RADS as highly applicable in practice.

CONCLUSIONS: ILD-RADS is reliable and valid among radiologists but requires further refinement to enhance consistency and applicability in diverse clinical settings. Moreover, pulmonologists support its use in clinical practice.

PMID:39908937 | DOI:10.1016/j.ejrad.2025.111961

Heliyon. 2024 Dec 30;11(2):e41311. doi: 10.1016/j.heliyon.2024.e41311. eCollection 2025 Jan 30.

ABSTRACT

Cumulative evidence suggests a link between specific autoimmune diseases (AD), including idiopathic inflammatory myopathies (IIM), and SARS-CoV-2 infection or COVID-19 vaccination. Anti-synthetase syndrome (ASS), a subset of IIM, is defined by the presence of autoantibodies against aminoacyl-tRNA synthetase (anti-ARS) and is strongly associated with interstitial lung disease (ILD), a major contributor to severe complications and reduced survival. We present four clinical cases of patients who developed autoantibodies against threonyl (PL-7) and alanyl (PL-12) synthetases associated with ASS-ILD shortly after SARS-CoV-2 infection or COVID-19 vaccination. Anti-ARS autoantibodies were identified using three complementary methods: immunoblotting, western blotting (WB) and the method considered the gold standard, immunoprecipitation (IP), which ensures accurate interpretation of results. The study highlights the clinical and pathogenic overlap between ASS-ILD and SARS-CoV-2-related lung involvement.Both conditions share similar high-resolution computed tomography (HRCT) patterns, including inflammation and pulmonary fibrosis (PF), driven by IFN-γ signaling, which complicates accurate diagnosis. Our results provide novel insights into the temporal association of SARS-CoV-2 and vaccine exposure with ASS-ILD, focusing on possible molecular mimicry between viral proteins and ARS molecules as a potential mechanism. Understanding the involvement of specific anti-ARS autoantibodies (PL-7 and PL-12) and the identification of genetic predispositions (HLA-B∗08:01 and HLA-DRB1∗03:01) in these patients may be key to underpinning these autoimmune manifestations. The study underscores the importance of a multidisciplinary approach and vigilant follow-up to optimize diagnosis and management. Further research is essential to elucidate the causal relationships and molecular mechanisms behind these observations.

PMID:39906838 | PMC:PMC11791273 | DOI:10.1016/j.heliyon.2024.e41311

Respirology. 2025 Feb 4. doi: 10.1111/resp.14892. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Fibrotic interstitial lung disease (ILD) is associated with high morbidity and mortality. Patients often exhibit impaired nutritional status and alterations in body composition, such as dynapenia and sarcopenia, which correlate with poor pulmonary function, reduced exercise tolerance and diminished quality of life. However, the impact of dynapenia and sarcopenia on prognosis has not been examined extensively in ILD patients. We assessed the impact of dynapenia and sarcopenia as risk factors for mortality and their prevalence in ILD.

METHODS: Prospective cohort study. ILD was classified into idiopathic pulmonary fibrosis (IPF), connective tissue disease-related ILD (CTD-ILD) and chronic hypersensitivity pneumonitis (CHP). Patients over 18 years old with a confirmed diagnosis of ILD were included, while those with diagnoses of cancer, human immunodeficiency virus and neurological disease were excluded. Dynapenia and sarcopenia were determined according to EWGSOP2 criteria.

RESULTS: Ninety-eight ILD patients were included; 33.66% had IPF, 47.96% had CTD-ILD, and 18.37% had CHP. The mean age was 63.89 ± 12.02 years; 37.76% were male. The risk factors associated with mortality included dynapenia (HR: 2.04, 95% CI: 1.10-3.77, p = 0.022), sarcopenia (HR: 1.88, 95% CI; 1.00-3.33, p = 0.049) and exercise tolerance (HR: 0.99, 95% CI; 0.99-0.99, p = 0.023), adjusted for confounding variables. The prevalence of dynapenia was 45% in ILD; 51% in IPF, 35% in CTD-ILD and 61% in CHP. The prevalence of sarcopenia was 29%; both IPF (39%) and CHP (50%) had a higher prevalence of sarcopenia than CTD-ILD (14%).

CONCLUSION: Sarcopenia and dynapenia are independent risk factors for mortality in ILD.

PMID:39905591 | DOI:10.1111/resp.14892

BMC Pulm Med. 2025 Feb 4;25(1):61. doi: 10.1186/s12890-025-03521-3.

ABSTRACT

BACKGROUND: Early identification of functional decline in fibrotic interstitial lung disease (F-ILD) is crucial for timely treatment and improved survival. While the 6-minute walk test (6MWT) is the standard for functional evaluation, it has practical limitations. The 1-minute sit-to-stand test (1MSTS) offers a simpler alternative; however, its correlation with the 6MWT in F-ILD patients remains unclear. This study aims to establish reference values for the 1MSTS in assessing functional capacity, evaluate its correlation with the 6MWT, and explore its utility in predicting 18-month mortality in F-ILD patients.

METHODS: This prospective study enrolled participants diagnosed with F-ILD based on multidisciplinary team discussions. Assessments included the 1MSTS, 6MWT, pulmonary function test (PFT), GAP score, mMRC scale, and Charlson Comorbidity Index (CCI). The association between 1MSTS repetitions and other variables was calculated using Spearman's rho. Bland-Altman plots assessed the agreement between 1MSTS repetitions and the 6MWT. Predictors of 18-month mortality were evaluated using ROC curve and Kaplan-Meier curve.

RESULTS: Of the 150 F-ILD patients, 37 (24.6%) had idiopathic pulmonary fibrosis (IPF), and 113 (75.4%) had connective tissue disease-related ILD (CTD-ILD). Using ≤ 23 repetitions as the cutoff for functional impairment in 1MSTS, 74 (47.3%) patients were classified as impaired. The 1MSTS significantly predicted 18-month mortality and demonstrated moderate correlations with GAP score (rs = -0.49), mMRC scale (rs = -0.47), and 6MWT distance (rs = 0.65). Bland-Altman analysis indicated agreement between 1MSTS repetitions and 6MWT distance. Using ≤ 23 repetitions as the cutoff value for the 1MSTS to predict 18-month mortality, the mortality rate was 76.4%, with an AUC of 0.81.

CONCLUSIONS: The findings suggest that ≤ 23 repetitions in the 1MSTS can serve as an indicator of functional impairment, demonstrate a good correlation with 6MWT distance, and effectively predict 18-month mortality in patients with F-ILD.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:39905346 | DOI:10.1186/s12890-025-03521-3

Radiology. 2025 Feb;314(2):e241001. doi: 10.1148/radiol.241001.

ABSTRACT

Background Prognostic value of radiologic features in interstitial lung disease (ILD) has been predominantly studied in idiopathic pulmonary fibrosis, but findings vary. The relative importance of features versus guideline-defined patterns in predicting outcomes is unknown. Purpose To identify radiologic features that are independently associated with transplant-free survival beyond clinical predictive factors across all ILD subtypes, and to identify whether individual features versus patterns are more important for prognostication. Materials and Methods This is a secondary analysis of the prospective Canadian Registry for Pulmonary Fibrosis. Consecutive patients with ILD were evaluated in standardized multidisciplinary discussions between January 2021 and March 2022. Radiologic features on thin-section CT images were quantified, and guideline-defined usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP) patterns were assigned. Multivariable Cox analysis was used to assess the associations of radiologic features with transplant-free survival, and nested models were used to test the relative importance of features compared with patterns. Results A total of 1593 patients (mean age, 66 years ± 12 [SD]; 800 male) were included. The following four features were associated with transplant-free survival: extent of honeycombing (hazard ratio, 1.20; 95% CI; 1.06, 1.36 per 10% increase in lung involvement; P = .005), extent of traction bronchiectasis (hazard ratio, 1.18; 95% CI: 1.10, 1.26 per 10% increase; P < .001), pulmonary artery diameter (hazard ratio, 1.03; 95% CI: 1.01; 1.04 per 1-mm increase; P = .002), and presence of subpleural sparing (hazard ratio, 0.76; 95% CI: 0.56, 0.96; P = .03). Guideline-defined patterns were not independently associated with survival in a model that included these four radiologic features, each of which retained its prognostic value. Conclusion The extent of fibrosis was predictive of worse outcomes across all ILD subtypes in a dose-dependent fashion and independent of well-recognized clinical prognostic factors. Guideline-defined UIP and fHP patterns each helped risk-stratify patients in isolation but lost prognostic value when accounting for the extent of fibrosis, suggesting that their previous association with mortality is based on these patterns acting as surrogates for a greater extent of fibrosis. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Wells in this issue.

PMID:39903073 | DOI:10.1148/radiol.241001

Pulm Circ. 2025 Feb 2;15(1):e70046. doi: 10.1002/pul2.70046. eCollection 2025 Jan.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a leading indication for lung transplantation. Pulmonary hypertension (PH), a common comorbidity in IPF, has gained renewed attention following the updated ESC/ERS guidelines, which redefine diagnostic thresholds for PH. This study evaluates the impact of the revised PH criteria on transplant waitlist outcomes among IPF patients. Specifically, we assessed the prevalence of PH under the new guidelines and its association with waitlist survival. We conducted a retrospective analysis using the OPTN/SRTR database, including 14,156 IPF candidates listed for lung transplantation. Survival analyses were performed using Kaplan-Meier and multivariate models to examine the influence of revised mPAP and PVR thresholds on waitlist mortality. The prevalence of PH, defined by the revised criteria, was significantly higher compared to the prior definition. Kaplan-Meier analysis demonstrated worse waitlist survival for patients with PH under both diagnostic thresholds. However, multivariate analysis revealed that mPAP and PVR thresholds were not independently predictive of mortality. Instead, clinical parameters, including 6MWD, functional status, BMI, FVC, PaCO2, and double lung transplant preference, were significant predictors of waitlist mortality. In conclusion, while the revised PH diagnostic criteria increase PH prevalence in IPF patients, their independent prognostic utility for waitlist survival is limited. This national transplant database study underscores the importance of comprehensive clinical evaluation and timely referral for transplantation in managing IPF with PH.

PMID:39902292 | PMC:PMC11788316 | DOI:10.1002/pul2.70046

Pediatr Emerg Care. 2025 Feb 4. doi: 10.1097/PEC.0000000000003343. Online ahead of print.

ABSTRACT

Restrictive cardiomyopathy is a rare form of cardiomyopathy in children, representing only 2.5%-3% of all pediatric cardiomyopathies, and is typically diagnosed between the ages of 6 and 10. The underlying etiology varies depending on age and region; however, idiopathic, genetic, and endomyocardial fibrosis are among the most common. Cohort studies have demonstrated mortality as high as 50% within 2 years of diagnosis, as well as high rates of adverse events including thromboembolism, pulmonary hypertension, and sudden cardiac death. There is a paucity of literature on point-of-care ultrasound (POCUS) for the diagnosis of pediatric restrictive cardiomyopathy. We present a case of a 3-year-old female whose diagnosis of heart failure was rapidly identified via POCUS which subsequently expedited life-saving treatment.

PMID:39901796 | DOI:10.1097/PEC.0000000000003343

Sci Rep. 2025 Feb 3;15(1):4120. doi: 10.1038/s41598-024-76561-0.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive scarring and fibrosis due to the abnormal accumulation of extracellular matrix components, primarily collagen. This study aims to design and solve an optimal control problem to regulate M2 macrophage activity in IPF, thereby preventing fibrosis formation by controlling the anti-M1 agent. The research models the diffusion of M2 macrophages in inflamed tissue using a novel dynamical system with partial differential equation (PDE) constraints. The control problem is formulated to minimize fibrosis by regulating an anti-M1 agent. The study employs a two-step process of discretization followed by optimization, utilizing the Galerkin spectral method to transform the M2 diffusion PDE into an algebraic system of ordinary differential equations (ODEs). The optimal control problem is then solved using Pontryagin/s minimum principle, canonical Hamiltonian equations, and extended Riccati differential equations. The numerical simulations indicate that without control, M2 macrophage levels increase and stabilize, contributing to fibrosis. In contrast, the optimal control strategy effectively reduces M2 macrophages, preventing fibrosis formation within 120 days. The results highlight the potential of the proposed optimal control approach in modulating tissue repair processes and mitigating the progression of IPF. This study underscores the significance of targeting M2 macrophages and employing mathematical methods to develop innovative therapies for lung fibrosis.

PMID:39900943 | DOI:10.1038/s41598-024-76561-0

Nat Commun. 2025 Feb 3;16(1):1303. doi: 10.1038/s41467-025-56501-w.

ABSTRACT

Irreversible damage of the lung epithelium in idiopathic pulmonary fibrosis (IPF) patients causes high mortality worldwide, with no lung repair approaches available currently. Here we show that in murine and monkey models, the KRT5+ P63+ progenitor cells in airway basal layer can enter the alveolar area post fibrotic injury. Aided with an automated culture system, we clone and characterize airway basal progenitor cells from 44 donors with various lung conditions. Transplantation of human progenitor cells into the mouse lung efficiently re-epithelializes the injured alveolar area, forms new respiratory tract and saccule-like structures, which ameliorates fibrotic lesions and improves survival of mice. Mechanistically, the engrafted human progenitor cells do not function by differentiating into mature alveolar cells in mouse lung; instead, they differentiate into saccular cells expressing multiple tight junction proteins such as CLDN4, which help the lung to re-establish epithelial barriers. Furthermore, by cloning P63+ airway basal progenitors from larger mammals and birds, we construct multiple lung-chimerism animals and uncover the evolutionarily conserved roles of these progenitor cells in lung repair. Overall, our data highlight the fate of airway basal progenitor cells in fibrotic lung and provide a potential therapeutic strategy for pulmonary diseases that lack inherent recovery mechanisms.

PMID:39900892 | DOI:10.1038/s41467-025-56501-w

OMICS. 2025 Feb 3. doi: 10.1089/omi.2024.0213. Online ahead of print.

ABSTRACT

Innovation in drug discovery for human diseases stands to benefit from systems science and next-generation phenomics approaches. An example is idiopathic pulmonary fibrosis (IPF) that is a chronic pulmonary disorder leading to respiratory failure and for which preventive and therapeutic medicines are sorely needed. Matrix metalloproteinases (MMPs), particularly MMP1 and MMP7, have been associated with IPF pathogenesis and are thus relevant to IPF drug discovery. This study evaluates the comparative therapeutic potentials of doxycycline, pirfenidone, and nintedanib in relation to MMP1 and MMP7 using molecular docking, molecular dynamics simulations, and a next-generation phenomics approach. Adsorption, distribution, metabolism, excretion, and toxicity analysis revealed that doxycycline and nintedanib adhered to Lipinski's rule of five, while pirfenidone exhibited no violations. The toxicity analysis revealed favorable safety profiles, with lethal dose 50 values of doxycycline, pirfenidone, and nintedanib being 2240kg, 580, and 500 mg/kg, respectively. Homology modeling validated the accuracy of the structures of the target proteins, that is, MMP1 and MMP7. The Protein Contacts Atlas tool, a next-generation phenomics platform that broadens the scope of phenomics research, was employed to visualize protein contacts at atomic levels, revealing interaction surfaces in MMP1 and MMP7. Docking studies revealed that nintedanib exhibited superior binding affinities with the candidate proteins (-6.9 kcal/mol for MMP1 and -7.9 kcal/mol for MMP7) compared with doxycycline and pirfenidone. Molecular dynamics simulations further demonstrated the stability of protein-ligand complexes. These findings highlight the notable potential of nintedanib in relation to future IPF therapeutics innovation. By integrating in silico and a next-generation phenomics approach, this study opens up new avenues for drug discovery and development for IPF and possibly, for precision/personalized medicines that consider the molecular signatures of therapeutic candidates for each patient.

PMID:39899320 | DOI:10.1089/omi.2024.0213

Front Immunol. 2025 Jan 17;15:1437984. doi: 10.3389/fimmu.2024.1437984. eCollection 2024.

ABSTRACT

BACKGROUND: Growing evidence indicates an association between circulating immune cell phenotypes and idiopathic pulmonary fibrosis (IPF). Although studies have attempted to elucidate the causal relationship between the two, further clarification of the specific mechanisms and causal linkages is warranted.

OBJECTIVE: We aimed to conduct a two-sample Mendelian randomization (MR) analysis with transcriptomics data analysis to elucidate the causal relationship between circulating immune cells and IPF and to explore potential biomarkers.

METHODS: We first explored the bidirectional causal association between IPF and immune cell phenotypes using two-sample MR analysis. Genome-wide association studies data for immune cell phenotype and IPF were obtained from publicly available databases. A standardized instrumental variable screening process was used to select single nucleotide polymorphisms (SNPs) for inclusion in the MR. Five methods represented by IVW were used to assess causal effects. Subsequently, SNP-nearest genes combined with the transcriptomics data of IPF were subjected to multiple bioinformatics analyses such as TIMER, WGCNA, functional enrichment analysis, protein-protein interaction analysis, and ROC to identify IPF biomarkers. Finally, the single-cell RNA sequencing (scRNA-seq) data was used to validate our findings by single-cell analysis.

RESULTS: The MR study identified 27 immune cell phenotypes causally associated with IPF, of which 20 were associated with a decreased risk of developing IPF and 7 were associated with an increased risk. CTSB (AUC=0.98), IL10 (AUC=0.83), and AGER (AUC=0.87) were identified as promising biomarkers of IPF. Single cell analysis showed differences in CD14+ CD16+ monocytes, CD16+ monocytes and Granulocyte-monocyte progenito between the IPF group and the healthy control group. The three hub genes were highly expressed in three immune cell subsets of IPF patients. It underscores the potential feasibility of three genes as biomarkers.

CONCLUSIONS: Our study demonstrates the causal associations of specific immune cell phenotypes with IPF through genetic methods and identifies CTSB, IL10, and AGER as biomarkers of IPF through bioinformatics analysis. These findings provide guidance for future clinical and basic research.

PMID:39896814 | PMC:PMC11782250 | DOI:10.3389/fimmu.2024.1437984

Cell Signal. 2025 Jan 30:111635. doi: 10.1016/j.cellsig.2025.111635. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a terminal lung disease with high mortality rate. Although Nintedanib (Nin) is an effective treatment for IPF, its precise mechanism of action remains unclear. In this study, we performed an integrated analysis of single-cell sequencing and RNA-seq data from lung tissues of both fibrotic and Nin-treated fibrotic mice to uncover new therapeutic mechanisms of Nin in IPF. Our results revealed an increase in interstitial macrophages following bleomycin (BLM) treatment. We used Monocle2, Cellchat, and in vivo experiments to demonstrate that Nin can inhibit Clec7a in interstitial macrophages, thereby suppressing the SPP1-mediated profibrotic pathway. Additionally, we utilized Scenic to predict transcription factors and identified NFκB as a major transcription factor in interstitial macrophages. In the in vitro experiments, we found that inhibiting Clec7a improved the secretion of SPP1 by M2 macrophages through the NFκB pathway. In subsequent in vivo experiments, we found that inhibiting of Clec7a improves pulmonary fibrosis through the NFκB/SPP1 pathway, and Nin alleviated BLM-induced pulmonary fibrosis by inhibiting Clec7a in interstitial macrophages. In summary, our study indicates that interstitial macrophages are upregulated in pulmonary fibrosis, and Nin reduces fibrosis by inhibiting Clec7a in interstitial macrophages, which in turn diminishes the NFκB /SPP1 pathway. These findings provided a new perspective on the mechanism of action of Nin in treating pulmonary fibrosis.

PMID:39892726 | DOI:10.1016/j.cellsig.2025.111635

Respir Investig. 2025 Jan 31;63(2):216-223. doi: 10.1016/j.resinv.2025.01.007. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic interstitial pneumonias (IIPs) may remain unclassifiable owing to inadequate, nonspecific, or conflicting clinical, radiological, or histopathological findings despite multidisciplinary discussion (MDD). Unclassifiable IIP (UCIIP) is a heterogeneous disease that can present with progressive pulmonary fibrosis (PPF). This study aimed to investigate the prevalence and clinical features of PPF in patients with UCIIP.

METHODS: In this post hoc analysis of a prospective multicenter registry of 222 patients with IIPs, 71 with UCIIP diagnosed using MDD were enrolled. PPF was defined based on worsening symptoms and radiological and physiological progression using the guideline criteria within 12 months or the criteria from the INBUILD trial within 24 months.

RESULTS: The median age was 72 years, and surgical lung biopsy was performed in 19.7%. Of the 66 patients with adequate follow-up data, 30 (45.5%) met either criterion and were diagnosed with PPF. UCIIP patients with PPF had significantly higher serum surfactant protein-D level and percentage of bronchoalveolar fluid neutrophils, lower %forced vital capacity and %diffusing capacity for carbon monoxide, and a higher proportion of honeycombing on high-resolution computed tomography and desaturation on exertion than those without PPF. Additionally, they had significantly more anti-fibrotic therapy and long-term oxygen therapy, a higher incidence of acute exacerbation, and a poorer prognosis than those without PPF. Cox proportional hazards analysis revealed that PPF was a significant poor prognostic factor, regardless of the criteria.

CONCLUSIONS: PPF is common and associated with poor prognosis in patients with UCIIP. Appropriate evaluation and management of PPF are essential for UCIIP.

PMID:39892159 | DOI:10.1016/j.resinv.2025.01.007

BMC Pulm Med. 2025 Jan 31;25(1):52. doi: 10.1186/s12890-025-03522-2.

ABSTRACT

BACKGROUND: Pulmonary fibrosis is characterized by the destruction of normal lung tissue and then replacement by abnormal fibrous tissue, leading to an overall decrease in gas exchange function. The effective treatment for pulmonary fibrosis remains unknown. The upstream pathogenesis of pulmonary fibrosis may involve cellular senescence of the lung tissue. Previously, a new gene therapy technology using Box A of the HMGB1 plasmid (Box A) was used to reverse cellular senescence and cure liver fibrosis in aged rats.

METHODS: Here, we show that Box A is a promising medicine for the treatment of lung fibrosis. In a bleomycin-induced pulmonary fibrosis model in the male Wistar rats, Student's t-test and one-way ANOVA were used to compare groups of samples.

RESULTS: Box A effectively lowered fibrous tissue deposits (from 18.74 ± 0.62 to 3.45 ± 1.19%) and senescent cells (from 3.74 ± 0.40% to 0.89 ± 0.18%) to levels comparable to those of the negative control group. Moreover, after eight weeks, Box A also increased the production of the surfactant protein C (from 3.60 ± 1.68% to 6.82 ± 0.65%).

CONCLUSIONS: Our results demonstrate that Box A is a promising therapeutic approach for pulmonary fibrosis and other senescence-promoted fibrotic lesions.

PMID:39891078 | DOI:10.1186/s12890-025-03522-2

J Biotechnol. 2025 Jan 29:S0168-1656(25)00025-2. doi: 10.1016/j.jbiotec.2025.01.019. Online ahead of print.

ABSTRACT

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most common chronic liver disease worldwide, affecting more than 30 percent of adults. The most severe form of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by necrotizing inflammation and rapid fibrosis progression, often leading to cirrhosis and hepatocellular carcinoma. Currently, only Resmetirom is approved for the treatment of MASH one of the main reasons is the absence of representative in vivo or in vitro models for MASH. To address this challenge, we developed a high-throughput 3D spheroid model consisting of human hepatocellular carcinoma cells (HepG2) and human hepatic stellate cells (LX-2) on microwell arrays. This model, induced with free fatty acids (FFA) to simulate steatosis and fibrosis, enables the assessment of efficacy and mechanisms for potential anti-MASH drugs. Our findings demonstrate that this in vitro spheroid model replicates key pathological features of human MASLD, including steatosis, oxidative stress, and fibrosis. Upon validation, we selected pirfenidone (PFD) and yinfenidone (AC-003), which are commonly used to treat idiopathic pulmonary fibrosis (IPF), to test their anti-MASH efficacy. Treatment with these drugs showed that they could regulate lipid synthesis and metabolism genes, reduce lipid accumulation, oxidative stress, and fibrosis levels. This 3D spheroid model represents a straightforward and efficient tool for screening anti-MASH drugs and investigating the molecular mechanisms of drug action.

PMID:39889902 | DOI:10.1016/j.jbiotec.2025.01.019

Clin Transl Med. 2025 Feb;15(2):e70217. doi: 10.1002/ctm2.70217.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease driven by both environmental and genetic factors. Epigenetics refers to changes in gene expression or cellular phenotype that do not involve alterations to DNA sequence. KMT2A is a member of the SET family which catalyses H3K4 methylation.

RESULTS: Through microarray and single-cell sequencing data, we discovered KMT2A-positive fibroblasts were increased in IPF lung tissues. KMT2A level was increased in IPF and bleomycin-induced pulmonary fibrosis mice lung tissues collected in our centre. Mice with AAV6-induced KMT2A knockdown in fibroblast showed attenuated pulmonary fibrosis after bleomycin treatment. Bioinformation also revealed that transcription factor PU.1 was a target of KMT2A. We demonstrated that PU.1 levels were increased in IPF tissues, bleomycin-induced mice lung tissues and primary fibrotic fibroblasts. KMT2A knockdown decreases PU.1 expression in vitro while KMT2A overexpression induces PU.1 activation. PU.1 fibroblast-specific knockout mice showed attenuated lung fibrosis induced by bleomycin. Furthermore, we demonstrated KMT2A up-regulated PU.1 in fibroblasts by catalysing H3K4me3 at the promoter of the PU.1 gene. The KMT2A transcription complex inhibitor mm102 treatment attenuated bleomycin-induced pulmonary fibrosis.

CONCLUSION: The current study indicated that histone modification participates in the pathogenesis of IPF and KMT2A may have the potential to be a therapeutic target of IPF treatment.

KEY POINTS: KMT2A plays a role in pulmonary fibrogenesis. KMT2A regulates PU.1 transcription in fibroblasts through H3K4me3 at promoter. KMT2A inhibitor attenuates pulmonary fibrosis in mice.

PMID:39888275 | DOI:10.1002/ctm2.70217

ChemMedChem. 2025 Jan 30:e202401001. doi: 10.1002/cmdc.202401001. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic interstitial lung disease characterized by irreversible loss of lung function and a poor prognosis. Type I collagen, a major component of the extracellular matrix, plays a central role in the pathogenesis of fibrosis and is considered a key molecular target for therapeutic intervention. While current anti-fibrotic therapies demonstrate limited efficacy in slowing disease progression, their clinical impact remains suboptimal due to poor pharmacokinetic properties and non-curative therapy. Moreover, the development of effective anti-fibrotic agents targeting collagen synthesis is hindered by the absence of robust, cost-effective, high-throughput drug screening platforms. In this study, we established a novel screening system designed to identify small molecules that inhibit the expression of the COL1A2 gene, which encodes type I collagen. Utilizing this system, we screened a library of natural and synthetic compounds developed at Nagasaki University and identified lamellarin D as a potent inhibitor of COL1A2 expression and subsequent type I collagen production. These findings suggest that lamellarin D, through its unique molecular mechanism, may serve as the foundation for the development of a new class of IPF treatments aimed at targeting the underlying fibrotic processes.

PMID:39887929 | DOI:10.1002/cmdc.202401001

Drug Metab Dispos. 2025 Jan;53(1):100010. doi: 10.1124/dmd.124.001917. Epub 2024 Nov 22.

ABSTRACT

Pirfenidone (PIR) is used in the treatment of idiopathic pulmonary fibrosis. After oral administration, it is metabolized by cytochrome P450 1A2 to 5-hydroxylpirfenidone (5-OH PIR) and further oxidized to 5-carboxylpirfenidone (5-COOH PIR), a major metabolite excreted in the urine (90% of the dose). This study aimed to identify enzymes that catalyze the formation of 5-COOH PIR from 5-OH PIR in the human liver. 5-COOH PIR was formed from 5-OH PIR in the presence of NAD+ by human liver microsomes (HLMs) more than by human liver cytosol (HLC), with the concomitant formation of the aldehyde form (5-CHO PIR) as an intermediate metabolite. By purifying enzymes from HLMs, alcohol dehydrogenases (ADHs) were identified as candidate enzymes catalyzing 5-CHO PIR formation, although ADHs are localized in the cytoplasm. Among constructed recombinant ADH1-5 expressed in HEK293T cells, only ADH4 efficiently catalyzed 5-CHO PIR formation from 5-OH PIR with a Km value (29.0 ± 4.9 μM), which was close to that by HLMs (59.1 ± 4.6 μM). In contrast to commercially available HLC, HLC prepared in-house clearly showed substantial 5-CHO PIR formation, and ADH4 protein levels were significantly (rs = 0.772, P < .0001) correlated with 5-CHO PIR formation in 25 HLC samples prepared in-house. Some components of the commercially available HLC may inhibit ADH4 activity. Disulfiram, an inhibitor of aldehyde dehydrogenases (ALDH), decreased 5-COOH PIR formation and increased 5-CHO PIR formation from 5-OH PIR in HLMs. ALDH2 knockdown in HepG2 cells by siRNA decreased 5-COOH PIR formation by 61%. SIGNIFICANCE STATEMENT: This study clarified that 5-carboxylpirfenidone formation from 5-hydroxylpirfenidone proceeds via a 2-step oxidation reaction catalyzed by ADH4 and disulfiram-sensitive enzymes, including ALDH2. Interindividual differences in the expression levels or functions of these enzymes could cause variations in the pharmacokinetics of pirfenidone.

PMID:39884816 | DOI:10.1124/dmd.124.001917