Am J Respir Cell Mol Biol. 2025 Apr 16. doi: 10.1165/rcmb.2024-0614OC. Online ahead of print.

ABSTRACT

The quest for innovative pharmacologic interventions in idiopathic pulmonary fibrosis (IPF) is a challenging journey. The complexity of the disease demands a comprehensive approach targeting multiple cell types and pathways. This study examined the antifibrotic properties of nerandomilast, a preferential phosphodiesterase 4B inhibitor, focusing on its effects on myofibroblasts (MF)s and endothelial cells. Using cytokine-stimulated human IPF lung fibroblasts (IPF-HLF) and RNA-seq, we assessed the effect nerandomilast has on MF contractility, MF markers and differentiation mechanisms. In addition, using human microvascular endothelial cells, endothelial barrier integrity and monocyte adhesion were assessed in a 3D microfluidic chip. Our results show that nerandomilast significantly inhibited MF contractility and marker expression in cytokine-stimulated IPF-HLF cells. Treatment with nerandomilast significantly activated cAMP-associated pathways and G-protein-coupled receptor (GPCR) signaling events while inhibiting mitogen-activated protein kinase (MAPK) signaling pathways and transforming growth factor beta (TGFβ) signaling. Nerandomilast also significantly reduced microvascular permeability in cytokine-stimulated human lung microvascular endothelial cells. Finally, in an adeno-associated virus-human diphtheria toxin receptor/diphtheria toxin mouse model of acute lung injury, nerandomilast significantly inhibited total protein in lavage, total macrophages, neutrophils, cell count and VCAM-1 expression. In summary, our results demonstrate that nerandomilast induces the dedifferentiation of human IPF lung MFs and diminishes their contractility in vitro by interfering with TGFβ, MAPK phosphatase-1 and GPCR signaling pathways. It also mitigates vascular dysfunction by strengthening endothelial junctions and inhibiting adhesion protein expression. These findings highlight nerandomilast's potential therapeutic use in IPF by providing insights into its cellular and molecular actions. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:40239038 | DOI:10.1165/rcmb.2024-0614OC

Am J Respir Cell Mol Biol. 2025 Apr 16. doi: 10.1165/rcmb.2024-0433OC. Online ahead of print.

ABSTRACT

Infection by influenza A virus (IAV) and other viruses causes disease exacerbations in chronic obstructive pulmonary disease (COPD). Immune responses are blunted in COPD, a deficit compounded by current standard-of-care glucocorticosteroids (GCS) to further predispose patients to life-threatening infections. The immunosuppressive effects of elevated transforming growth factor-beta (TGF-β) in COPD may amplify lung inflammation during infections whilst advancing fibrosis. In the current study, we investigated potential repurposing of pirfenidone, currently used as an anti-fibrotic for idiopathic pulmonary fibrosis, as a non-steroidal treatment for viral exacerbations of COPD. Murine models of lung-specific TGF-β overexpression or chronic cigarette smoke exposure with IAV infection were used. Pirfenidone was administered daily by oral gavage commencing pre-or post-infection, while inhaled pirfenidone and GCS treatment pre-infection were also compared. Tissue and bronchoalveolar lavage were assessed for viral replication, inflammation and immune responses. Overexpression of TGF-β enhanced severity of IAV infection contributing to unrestrained airway inflammation. Mechanistically, TGF-β reduced innate immune responses to IAV by blunting interferon regulated gene (IRG) expression and suppressing production of anti-viral proteins. Prophylactic pirfenidone administration opposed these actions of TGF-β, curbing IAV infection and airway inflammation associated with TGF-β overexpression and cigarette smoke-induced COPD. Notably, inhaled pirfenidone caused greater inhibition of viral loads and inflammation than inhaled GCS. These proof-of-concept studies demonstrate that repurposing pirfenidone and employing a preventative strategy may yield substantial benefit over anti-inflammatory GCS in COPD. Pirfenidone can mitigate damaging virus exacerbations without attendant immunosuppressive actions and merits further investigation, particularly as an inhaled formulation.

PMID:40239009 | DOI:10.1165/rcmb.2024-0433OC

Ann Thorac Med. 2025 Apr-Jun;20(2):98-107. doi: 10.4103/atm.atm_213_24. Epub 2025 Mar 31.

ABSTRACT

BACKGROUND: There are still disagreements about diagnostic criteria and treatment of progressive pulmonary fibrosis (PPF). Real-life data and survival analyses have a guiding role in clarifying this issue.

METHODS: In this multicenter retrospective cohort study, real-life data of adult patients diagnosed with PPF and treated with antifibrotics for at least 6 months were examined.

RESULTS: Of the 222 patients, 161 were treated with Nintedanib (N) and 61 with Pirfenidone (P). The most common PPF subtype was connective tissue disease-related interstitial lung disease (CTD-ILD) (53.2%). The progression rate was significantly higher in patients with usual interstitial pneumonia (UIP) (P = 0.003). A -3.1% (-49.2 ml) decrease was detected in forced vital capacity (FVC) in the 6th month. The 6th month and overall progression-free survival (PFS) rates were 83.3% and 51.8%. The 6th month and overall clinical event-free survival (CEFS) rates were 89.6% and 53.6%. The survival rates for 6th, 12th, and entire follow-up periods were found to be 98.2%, 89.2%, and 77.5%. CT-ILD had the longest survival time (166.5 ± 9.2 months) and fibrotic hypersensitivity pneumonia had the shortest survival time (87.6 ± 9.2 months) (P = 0.011). N was advantageous in patients with UIP in terms of FVC loss and estimated survival. While PFS during the entire follow-up period was in favor of N, CEFS had no significant difference between drugs.

CONCLUSION: PPF subtypes have significant differences in terms of prognosis and survival. The effect of AF drugs on progression varies, especially among radiological patterns. An individualized approach is required in the diagnosis, follow-up, and treatment of patients with PPF.

PMID:40236382 | PMC:PMC11996130 | DOI:10.4103/atm.atm_213_24

bioRxiv [Preprint]. 2025 Apr 6:2025.04.01.646600. doi: 10.1101/2025.04.01.646600.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease where excessive extracellular matrix (ECM) deposition and remodeling stiffens the lung, impeding its function. Many factors are known to contribute to the development of this fibrosis, but a lack of conclusive understanding endures because of their complex nature. The modification of ECM and the unique architecture of the lung are such factors in IPF's propagation and not solely casualties. Their effects on fibrogenesis are not known and tricky to study. We apply a computational methodology known as an agent-based model (ABM) to simulate cellular behavior as automata. Our ABM is a tissue maintenance model where agents modify tissue density to sustain a global mean and variance to represent the cyclic turnover of ECM. Agents traverse and interact with high fidelity architecture obtained through micro computed tomography (microCT) of mouse lung tissue. The properties of the ABM are validated to microCT of fibrotic mouse lung tissue. We find that increasing cell density is sufficient for fibrogenesis, but that the lung architecture led to more tissue deposition. Our model suggests that lung structure is a relevant contributor to the pathogenesis of IPF.

PMID:40236173 | PMC:PMC11996469 | DOI:10.1101/2025.04.01.646600

Health Expect. 2025 Apr;28(2):e70260. doi: 10.1111/hex.70260.

ABSTRACT

BACKGROUND: Research about patient engagement for people with rare diseases has identified how the experiences of some members of the public are overlooked in relation to clinical trial design and trial participation. As part of a knowledge transfer partnership (KTP), the authors were granted access to patient insight reports about the needs of people with idiopathic pulmonary fibrosis (IPF), to inform clinical trial design and marketing strategy. These were contrasted with data from qualitative interviews, informed by and collected from people with IPF and the clinical staff who recruit them to trials.

OBJECTIVE: To identify patient and professional perspectives for IPF drug trials to create opportunities for innovation in patient engagement.

DESIGN: Ethnography. Qualitative researcher embedded in a pharmaceutical organisation.

SETTING AND PARTICIPANTS: International patient insight reports to inform a clinical trial protocol (n = 1) and marketing strategy (n = 6), including the experiences of over 100 patients with IPF. In the United Kingdom, interviews with patients with IPF (n = 32) and the staff who support them clinically and recruit them to trials of new medicines (n = 19) at one specialist interstitial lung disease (ILD) centre.

RESULTS: Methodological practices inherent in inpatient insight reports ensured the perspectives of some people with IPF were overlooked. Interviews with a more marginalised population of people with IPF, and the staff who support them, identified that some found trial information confusing, trial practices frustrating and the opportunities to engage in trial design absent.

DISCUSSION: Current pharmaceutical practices of working with contract research organisations and patient organisations exclude the perspectives of patients with IPF who do not engage with either. Trial recruitment information needs to be tailored to the needs of individuals, and trial processes need to enable a wider group of patients to participate.

CONCLUSIONS: People with IPF want the opportunity to participate in drug trials and trial science. However, methodological rigour and deliberative practices are required to enable a wider group of patients to have a stake in the design and conduct of drug trials for rare diseases. The challenge now is for regulators to mandate such inclusive practices and for pharmaceutical organisations to adopt them.

PATIENT OR PUBLIC CONTRIBUTION: A Patient Advisory Group (PAG) comprising six people with IPF gave input on the research protocol and then on the scope and content of the ongoing research. Two patients from international patient organisations served as a Steering Group (SG). Members of these groups provided their interpretations of the study findings and gave insight on their experiences in clinical design and participation.

PMID:40235185 | DOI:10.1111/hex.70260

Orphanet J Rare Dis. 2025 Apr 15;20(1):180. doi: 10.1186/s13023-025-03695-3.

ABSTRACT

BACKGROUND: Fibrosing mediastinitis is a rare benign disease frequently complicated by pulmonary hypertension. A definitive diagnosis for fibrosing mediastinitis-associated pulmonary hypertension (FM-PH) and its etiologies necessitates mediastinal biopsy and subsequent pathological assessment. Endobronchial ultrasound (EBUS)-guided transbronchial mediastinal cryobiopsy is a recently developed technique that provides diagnostic advantages over standard needle biopsy, particularly in benign mediastinal disorders. Nevertheless, their safety and efficacy in diagnosing FM-PH remain elusive.

METHODS: We retrospectively studied patients with mediastinal lesion and pulmonary vascular compression who underwent both transbronchial needle aspiration and mediastinal cryobiopsy with EBUS guidance. Diagnostic yields of FM-PH and its etiologies, along with procedure-related adverse events, were analyzed. Immunohistochemical study was conducted to identify immunological properties of FM-PH.

RESULTS: Of the 529 patients with mediastinal lesions, 80 exhibited pulmonary vessel compression, including 10 who were ultimately diagnosed with FM-PH following mediastinal biopsy and right heart catheterization. Cryobiopsy showed a higher diagnostic yield for FM-PH compared to needle aspiration (100% versus 40%, p = 0.011). Disease etiologies included pneumoconiosis in 5 cases, tuberculosis in 3, and idiopathic FM-PH in the remaining 2. Cryobiopsy appeared to be superior to needle biopsy for etiological diagnosis, although this difference was not statistically significant (80% versus 60%, p = 0.628). Immunohistochemical analyses of cryosamples revealed mixed inflammatory infiltrates of B and T lymphocytes, as well as macrophages, surrounding or within FM-PH lesions. There was no significant bleeding or other complications.

CONCLUSION: Transbronchial mediastinal cryobiopsy might be a safe and effective diagnostic tool for FM-PH, offering valuable information for personalized treatment.

PMID:40234923 | DOI:10.1186/s13023-025-03695-3

Eur J Med Res. 2025 Apr 15;30(1):288. doi: 10.1186/s40001-025-02501-x.

ABSTRACT

BACKGROUND: The diagnosis of idiopathic pulmonary fibrosis (IPF) is complex, which requires lung biopsy, if necessary, and multidisciplinary discussions with specialists. Clinical diagnosis of the two ailments is particularly challenging due to the impact of interobserver variability. Several studies have endeavored to utilize image-based machine learning to diagnose IPF and its subtype of usual interstitial pneumonia (UIP). However, the diagnostic accuracy of this approach lacks evidence-based support.

OBJECTIVE: We conducted a systematic review and meta-analysis to explore the diagnostic efficiency of image-based machine learning (ML) for IPF.

DATA SOURCES AND METHODS: We comprehensively searched PubMed, Cochrane, Embase, and Web of Science databases up to August 24, 2024. During the meta-analysis, we carried out subgroup analyses by imaging source (computed radiography/computed tomography) and modeling type (deep learning/other) to evaluate its diagnostic performance for IPF.

RESULTS: The meta-analysis findings indicated that in the diagnosis of IPF, the C-index, sensitivity, and specificity of ML were 0.93 (95% CI 0.89-0.97), 0.79 (95% CI 0.73-0.83), and 0.84 (95% CI 0.79-0.88), respectively. The sensitivity of radiologists/clinicians in diagnosing IPF was 0.69 (95% CI 0.56-0.79), with a specificity of 0.93 (95% CI 0.74-0.98). For UIP diagnosis, the C-index of ML was 0.91 (95% CI 0.87-0.94), with a sensitivity of 0.92 (95% CI 0.80-0.97) and a specificity of 0.92 (95%CI 0.82-0.97). In contrast, the sensitivity of radiologists/clinicians in diagnosing UIP was 0.69 (95% CI 0.50-0.84), with a specificity of 0.90 (95% CI 0.82-0.94).

CONCLUSIONS: Image-based machine learning techniques demonstrate robust data processing and recognition capabilities, providing strong support for accurate diagnosis of idiopathic pulmonary fibrosis and usual interstitial pneumonia. Future multicenter large-scale studies are warranted to develop more intelligent evaluation tools to further enhance clinical diagnostic efficiency. Trial registration This study protocol was registered with PROSPERO (CRD42022383162).

PMID:40235000 | DOI:10.1186/s40001-025-02501-x

Thorax. 2025 Apr 15:thorax-2025-223299. doi: 10.1136/thorax-2025-223299. Online ahead of print.

NO ABSTRACT

PMID:40234006 | DOI:10.1136/thorax-2025-223299

ERJ Open Res. 2025 Apr 14;11(2):00745-2024. doi: 10.1183/23120541.00745-2024. eCollection 2025 Mar.

ABSTRACT

QUESTION: The reference test for the functional evaluation of pulmonary fibrosis (PF) during exercise is the 6-min walk test (6MWT). However, the 6MWT involves temporal and spatial constraints that the 1-min sit-to-stand test (1-MSTST) does not have. Previous studies have not validated 1-MSTST use in this context, mainly because of far less oxygen desaturation. We hypothesise that the modified 1-MSTST (m1-MSTST), taking into account the recovery phase, could compensate this shortcoming.

PATIENTS AND METHODS: This was a randomised, crossover, single-centre trial conducted in 36 patients with PF. A 6MWT and 1-MSTST were performed 30 min apart for each patient in a randomised order. An equivalence test was performed on the peripheral oxygen saturation (S pO2 ) nadir.

RESULTS: The 36 patients comprised eight with idiopathic PF, five with nonspecific idiopathic pneumonia, eight with collagen tissue disease-associated PF, four with hypersensitivity pneumonitis, two with sarcoidosis and nine with other PF. Mean±sd nadir desaturation was 84.9±4.3% for the 6MWT and 88±3.5% for the m1-MSTST, with a strong correlation between both tests. 33 patients (91.7%) had concordant results in the two tests regarding significant desaturation (S pO2 delta >4% or nadir <88%), which is a known prognosis factor.

CONCLUSION: The m1-MSTST, taking into account the recovery phase, is a sensible compromise to the 6MWT in measuring exercise performance in people with PF. As many clinical endpoints transfer from hospital to outpatient care, the m1-MSTST is technically easier and more practical for patients. Further studies are warranted to determine the minimal clinically important difference and norms in healthy subjects.

PMID:40230431 | PMC:PMC11995277 | DOI:10.1183/23120541.00745-2024

Front Cell Dev Biol. 2025 Mar 31;13:1535601. doi: 10.3389/fcell.2025.1535601. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease with an unknown origin and complex pathogenic mechanisms. A deeper understanding of these mechanisms is essential for effective treatment. Pulmonary fibrosis is associated with the senescence of alveolar type II epithelial (ATⅡ) cells. Additionally, ATⅡ senescence can lead to a senescence-associated secretory phenotype, which affects cellular communication and disrupts lung tissue repair, contributing to the development of IPF. The role of mitochondrial dysfunction in senescence-related diseases is increasingly recognized. It can induce ATⅡ senescence through apoptosis, impaired autophagy, and disrupted energy metabolism, potentially playing a key role in IPF progression. This article explores the therapeutic potential of targeting cellular senescence and mitochondrial dysfunction, emphasizing their significant roles in IPF pathogenesis.

PMID:40230412 | PMC:PMC11994736 | DOI:10.3389/fcell.2025.1535601

J Vis Exp. 2025 Mar 28;(217). doi: 10.3791/67565.

ABSTRACT

Lung transplantation is a critical treatment for patients with end-stage lung diseases like idiopathic pulmonary fibrosis, but challenges such as donor shortages and posttransplant complications persist. Bioengineered lungs, integrating patient-specific cells into decellularized animal scaffolds, present a promising alternative. Despite progress in using bioengineered lungs in animal models, functionality and structure remain immature. This protocol addresses a critical barrier in organ bioengineering: the need for a cost-effective experimental platform. By using mouse models instead of larger animals like rats or swine, researchers can significantly reduce the resources required for each experiment, accelerating research progress. The protocol outlines a detailed procedure for lung bioengineering using mouse heart-lung blocks and human primary cells, focusing on isolation strategy for the mouse heart-lung block, decellularization, bioreactor setup, perfusion-based organ culture, and orthotopic transplantation of bioengineered lungs. This mouse-scale platform not only reduces experimental costs but also provides a viable framework for optimizing cell types and numbers for recellularization, testing different cell types using histological and molecular methods, and ensuring blood flow post-transplantation. The method holds potential for broad applications, including studying cell interactions in three-dimensional culture conditions, cell-matrix interactions, and ex vivo cancer modeling, thereby advancing the field of organ bioengineering.

PMID:40228017 | DOI:10.3791/67565

Chin Med J Pulm Crit Care Med. 2025 Mar 7;3(1):12-21. doi: 10.1016/j.pccm.2025.02.001. eCollection 2025 Mar.

ABSTRACT

Significant advances have been made in diagnosing and treating idiopathic pulmonary fibrosis (IPF) in the last decade. The incidence and prevalence of IPF are increasing, and morbidity and mortality remain high despite the two Food and Drug Administration (FDA)-approved medications, pirfenidone and nintedanib. Hence, there is an urgent need to develop new diagnostic tools and effective therapeutics to improve early, accurate diagnosis of IPF and halt or reverse the progression of fibrosis with a better safety profile. New diagnostic tools such as transbronchial cryobiopsy and genomic classifier require less tissue and generally have good safety profiles, and they have been increasingly utilized in clinical practice. Advances in artificial intelligence-aided diagnostic software are promising, but challenges remain. Both pirfenidone and nintedanib focus on growth factor-activated pathways to inhibit fibroblast activation. Novel therapies targeting different pathways and cell types (immune and epithelial cells) are being investigated. Biomarker-based personalized medicine approaches are also in clinical trials. This review aims to summarize recent diagnostic and therapeutic development in IPF.

PMID:40226606 | PMC:PMC11993042 | DOI:10.1016/j.pccm.2025.02.001

J Thorac Dis. 2025 Mar 31;17(3):1364-1376. doi: 10.21037/jtd-24-1882. Epub 2025 Mar 14.

ABSTRACT

BACKGROUND: This study aims to elucidate the capability of periostin (POSTN) as a serum biomarker in diagnosing idiopathic pulmonary fibrosis (IPF), assessing disease severity, and predicting acute exacerbations of IPF (AE-IPF), and to compare it with traditional IPF serum biomarkers Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D).

METHODS: From October 2022 to October 2023, 55 patients who were diagnosed with IPF and treated at the Third Affiliated Hospital of Anhui Medical University were enrolled in the IPF group. Additionally, 30 patients with bacterial pneumonia (BP) and 30 healthy individuals were selected as the BP and healthy control (HC) groups, respectively. All participants underwent pulmonary function tests, and enzyme-linked immunosorbent assay (ELISA) was used to measure serum POSTN, KL-6, SP-A, and SP-D levels. IPF patients also underwent high-resolution computed tomography (HRCT) to quantify HRCT scores. Receiver operating characteristic (ROC) curves were plotted to obtain sensitivity and specificity. Binary logistic regression analysis was conducted to identify AE-IPF risk factors.

RESULTS: Serum POSTN, KL-6, SP-A, and SP-D concentrations were significantly greater in the IPF group than in the BP and HC groups (P<0.001), whereas serum SP-A and SP-D levels were greater in the BP group than in the HC group (P=0.001, P=0.04). The sensitivity of POSTN for diagnosing IPF is 94.5%, and the specificity is 93.3%, both of which are higher than those of KL-6, SP-A, and SP-D. Within the IPF group, serum POSTN levels were negatively correlated with the percentage of predicted forced expiratory volume in one second (FEV1%pred) (P=0.01) and the percentage of the predicted diffusing capacity for carbon monoxide (DLCO%pred) (P=0.003). Additionally, in IPF patients, serum POSTN, KL-6, and SP-A levels were significantly positively associated with HRCT scores. Logistic regression analysis indicated that decreased DLCO%pred and increased baseline serum KL-6 levels were both independent risk factors for AE-IPF.

CONCLUSIONS: POSTN is a valuable serum biomarker for IPF and has the highest sensitivity and specificity among the four serum markers, with a diagnostic performance superior to that of KL-6, SP-A, and SP-D. DLCO%pred and KL-6 have high predictive value for AE-IPF.

PMID:40223944 | PMC:PMC11986764 | DOI:10.21037/jtd-24-1882

Respirology. 2025 Apr 13. doi: 10.1111/resp.70043. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis is a progressive interstitial lung disease characterised by excessive activation of myofibroblasts. However, currently available antifibrotic drugs exhibit limited efficacy. The dysregulation of redox processes plays a significant role in the pathogenesis of idiopathic pulmonary fibrosis. Dextromethorphan (DM) is used in the treatment of various inflammation-related diseases. This study aimed to investigate the effectiveness of the combination of DM and pirfenidone (PFD) in treating idiopathic pulmonary fibrosis in both animal models and humans.

METHODS: In a bleomycin-induced pulmonary fibrosis mouse model, the anti-fibrotic effects of DM and/or PFD were assessed by evaluating fibrotic area, hydroxyproline levels, and fibrotic markers. In a transforming growth factor-β1-induced cell model, proliferation, migration, fibrosis markers, and oxidative stress were analysed to elucidate the mechanisms underlying the anti-fibrotic actions of DM and/or PFD. Finally, the efficacy of DM combined with PFD in patients with pulmonary fibrosis was evaluated by comparing pulmonary imaging scores and pulmonary function before and after treatment in the PFD group and the PFD + DM group.

RESULTS: We observed that even ultralow doses of DM, either alone or in combination with PFD, demonstrated substantial protective effects in mice. Notably, administration of DM or combined drugs at 2 weeks after bleomycin modelling still showed anti-fibrotic effects. In vitro, DM monotherapy and combination therapy restored the redox balance by suppressing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4/reactive oxygen species production and upregulating superoxide dismutase, contributing to their anti-fibrotic mechanisms. In the clinical study, add-on DM improved PFD in mitigating pulmonary function decline and improving chest high-resolution computed tomography imaging scores.

CONCLUSIONS: Ultralow doses of dextromethorphan significantly alleviate pulmonary fibrosis in bleomycin-treated mice through restoring the redox balance. Add-on DM improves the effects of PFD in both bleomycin-treated mice and patients with pulmonary fibrosis.

TRIAL REGISTRATION: ChiCTR2000037602.

PMID:40223283 | DOI:10.1111/resp.70043

Br J Pharmacol. 2025 Apr 13. doi: 10.1111/bph.70043. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Activation of the sphingosine-1-phosphate receptor-2 (S1P2 receptor) promotes idiopathic pulmonary fibrosis (IPF). However, the mechanisms associated with IPF development via S1P2 receptor signalling are poorly understood and no S1P2 receptor antagonists have been approved for clinical use.

EXPERIMENTAL APPROACH: Western blotting and immunohistochemical assays analysed inflammatory factors and epithelial-mesenchymal transition (EMT) markers. Co-immunoprecipitation and immunofluorescence analysed the binding of S1P2 receptor to dapper1 (Dpr1) and cyclic AMP response-binding protein 1 (CREB1). X-ray-based computed tomography diagnosed IPF in bleomycin (BLM)-treated mice. Barometric whole-body plethysmography tested pulmonary function of mice. Masson's trichrome and Sirius red staining analysed extracellular matrix deposition. Enzyme-linked immunosorbent assays analysed inflammatory factors and hydroxyproline.

KEY RESULTS: Activation of S1P2 receptors promoted IPF through the binding of S1P2 receptor to Dpr1, decreasing dishevelled (Dvl) degradation to accumulate β-catenin. The β-catenin accumulated in the nucleus, upregulating its target genes by binding to T-cell factor/lymphoid enhancer factor. The binding of S1P2 receptor to Dpr1 also led to S1P2 receptor translocation to the nucleus, where it promoted EMT by activating CREB1. BLM-induced IPF in mice was characterised by activated-S1P2 receptor signalling. Inhibition of S1P2 receptor prevented the binding of S1P2 receptor to Dpr1, resulting in decreased β-catenin accumulation and blocking nuclear translocation of S1P2 receptor. The S1P2 receptor antagonist S118 was more effective than pirfenidone in attenuating IPF through anti-inflammatory, anti-fibrosis, and anti-EMT effects.

CONCLUSIONS AND IMPLICATIONS: Activation of S1P2 receptors promotes IPF through the binding of S1P2 receptor to Dpr1 and the nuclear translocation of S1P2 receptor to activate CREB1. Thus, the S1P2 receptor antagonist S118 has potential clinical application in attenuating IPF.

PMID:40222913 | DOI:10.1111/bph.70043

Int Immunopharmacol. 2025 Apr 12;155:114653. doi: 10.1016/j.intimp.2025.114653. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease marked by increasing dyspnea and respiratory failure. The underlying mechanisms remain poorly understood, given the complexity of its pathogenesis. This review investigates the microenvironment of IPF to identify novel mechanisms and therapeutic avenues. Studies have revealed that various cell types, including alveolar epithelial cells, fibroblasts, myofibroblasts, and immune cells, are integral to disease progression, engaging in cellular stress responses and inflammatory regulation via signaling pathways such as TGF-β, Wnt, mTOR, and ROS. Non-coding RNAs, particularly miRNAs, are critical in IPF and may serve as diagnostic and prognostic biomarkers. Regarding treatment, mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) or non-vesicular derivatives offer promise by modulating immune responses, enhancing tissue repair, and inhibiting fibrosis. Additionally, alterations in the lung microbiota are increasingly recognized as a contributing factor to IPF progression, offering fresh insights into potential treatments. Despite the encouraging results of MSC-based therapies, the precise mechanisms and clinical applications remain subjects of ongoing research. This review emphasizes the significance of the IPF microenvironment and highlights the need for further exploration to develop effective therapies that could enhance patient outcomes.

PMID:40222273 | DOI:10.1016/j.intimp.2025.114653

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