Br J Hosp Med (Lond). 2025 Apr 25;86(4):1-22. doi: 10.12968/hmed.2024.0934. Epub 2025 Apr 21.

ABSTRACT

Aims/Background Idiopathic pulmonary fibrosis (IPF) is associated with an increased mortality risk. However, the factors that contribute to this risk remain unknown. This study aimed to systematically review existing predictive models for IPF-related mortality and to evaluate prognostic factors associated with patient outcomes. Methods A comprehensive literature search was conducted on PubMed, Cochrane Library, Web of Science, and Embase for studies on IPF mortality risk prediction models published between 1 January 1984 and 15 November 2024. Two independent reviewers screened, extracted, and cross-checked the data. The risk of bias and model applicability were also evaluated. Results A total of 17 risk prediction models were identified. The area under the receiver operating characteristic (ROC) curve (AUC) ranged from 0.728 to 0.907, while the model validation results ranged from 0.750 to 0.920. The concordance index (C-index) of 10 studies was more than 0.7, indicating good predictive performance. This study encompassed a total of 17 risk prediction models incorporating between 3 and 8 combined prognostic variables, with the most frequently included predictors being forced vital capacity as a percentage of the predicted value (FVC%pred), carbon monoxide diffusion capacity as a percentage of the predicted value (DLCO%pred), gender, age, six-minute walk test (6MWT) results, and dyspnea severity. Conclusion Current IPF mortality risk prediction models remain in an exploratory phase, with a generally high risk of bias. Furthermore, the lack of external validation in some models limits their generalizability. Future research should focus on improving the applicability of the model to enhance clinical application.

PMID:40265534 | DOI:10.12968/hmed.2024.0934

J Mass Spectrom. 2025 May;60(5):e5138. doi: 10.1002/jms.5138.

ABSTRACT

Pulmonary fibrosis (PF) is a chronic and progressive lung disease with fatal consequences. The study of PF is challenging due to the complex mechanism involved, the need to understand the heterogeneity and spatial organization within lung tissues. In this study, we investigate the metabolic heterogeneity between two forms of lung fibrosis: idiopathic pulmonary fibrosis (IPF) and silicosis, using advanced spatially-resolved metabolomics techniques. Employing high-resolution mass spectrometry imaging, we spatially mapped and identified over 260 metabolites in lung tissue sections from mouse models of IPF and silicosis. Histological analysis confirmed fibrosis in both models, with distinct pathological features: alveolar destruction and collagen deposition in IPF, and nodule formation in silicosis. Metabolomic analysis revealed significant differences between IPF and silicosis in key metabolic pathways, including phospholipid metabolism, purine/pyrimidine metabolism, and the TCA cycle. Notably, phosphocholine was elevated in silicosis but reduced in IPF, while carnitine levels decreased in both conditions. Additionally, glycolytic activity was increased in both models, but TCA cycle intermediates showed opposing trends. These findings highlight the spatial metabolic heterogeneity of PF and suggest potential metabolic targets for therapeutic intervention. Further investigation into the regulatory mechanisms behind these metabolic shifts may open new avenues for fibrosis treatment.

PMID:40264277 | DOI:10.1002/jms.5138

Intern Med J. 2025 Apr 22. doi: 10.1111/imj.70051. Online ahead of print.

ABSTRACT

Pulmonary fibrosis care, affecting both idiopathic pulmonary fibrosis and other forms of interstitial lung disease (ILD) characterised by fibrosis, has transformed with a range of innovations that affect the diagnosis, treatment and prognosis of this condition. Pharmacotherapeutic options have expanded, with increased indications for the application of effective antifibrotic therapy in non-IPF progressive pulmonary fibrosis as a solo treatment or combined with immunosuppression, emerging evidence for immunomodulatory therapy including biologic agents and greater access to clinical trials. The diagnostic approach to unclassifiable ILD now includes transbronchial lung cryobiopsy, a less invasive method to obtain histopathology with reduced morbidity and mortality compared to surgical lung biopsy. A multidisciplinary approach optimises the care of people with ILD and includes non-pharmacological management, addressing significant comorbidities, symptom care and advanced care planning. This review will summarise recent updates in pulmonary fibrosis management.

PMID:40260907 | DOI:10.1111/imj.70051

BMC Pulm Med. 2025 Apr 21;25(1):186. doi: 10.1186/s12890-025-03611-2.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a deadly respiratory disease of older patients. IPF therapies (antifibrotics) are efficacious in slowing disease progression, but they are critically underutilized. Potential barriers to antifibrotic use are polypharmacy and potentially inappropriate medications (PIM). We examined the frequency of these factors for older patients with IPF.

METHODS: We retrospectively analyzed records of Veterans ≥ 65 years old in the Durham Veterans Affairs Health Care System who received a diagnosis of IPF and received care between 11 April 2023 and 9 September 2024. We analyzed medication profiles from the Corporate Data Warehouse including total medication counts, polypharmacy (≥ 5 medications), severe polypharmacy (> 15 medications), and prescription of a PIM in the anticholinergic, antidepressant, sedative, and antipsychotic classes using published geriatric guidelines (2023 Beers criteria, Screening Tool of Older People's Potentially Inappropriate Prescriptions [STOPP] version 3). Identified PIMs underwent protocolized review to categorize them further as likely appropriate or inappropriate.

RESULTS: We identified 367 Veterans ≥ 65 years old with a diagnosis of IPF diagnostic during our study period. Total medication count was high for older Veterans (mean 14.2, SD 7.0). Veterans commonly had polypharmacy (350/367, 95.4%), severe polypharmacy (161/367, 43.9%), and ≥ 1 PIM (97/367, 26.4%). After protocolized review, 5.7% (21/367) of older Veterans with IPF had a likely inappropriate medication without documentation of a failed preferred alternative.

CONCLUSION: For older Veterans with IPF, polypharmacy and PIM use were common and represent likely barriers to effective IPF pharmacotherapy initiation. Interventions that target these factors like deprescribing could improve antifibrotic use.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:40259309 | DOI:10.1186/s12890-025-03611-2

Nat Commun. 2025 Apr 21;16(1):3748. doi: 10.1038/s41467-025-59093-7.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe lung disease occurring throughout the world; however, few clinical therapies are available for treating this disorder. Overactivated fibroblasts drive abnormal fibrosis accumulation to maintain dynamic balance between inflammation and extracellular matrix (ECM) stiffness. Given pulmonary cell can regenerate, the lung may possess self-repairing abilities if fibrosis is removed via clearance of overactivated fibroblasts. The aim of this study was to evaluate the therapeutic activity of transient antifibrotic chimeric antigen receptor (CAR) T cells (generated via a novelly-designed lipid nanoparticle-messenger RNA (LNP-mRNA) system) and explore the regeneration mechanisms of lung in a male mouse model of bleomycin-induced pulmonary fibrosis. Here we found that fibrosis-induced ECM stiffening impaired alveolar epithelial cell compensation. The proposed LNP-mRNA therapy eliminated overactivated fibroblasts to rescue pulmonary fibrosis. The restored ECM environment regulated the cellular profile. The elevated plasticity of AT2 and Pclaf+ cells increased AT1 cell population via polarization. Apoe+ macrophages and increased numbers of effector T cells were shown to reestablish pulmonary immunity. Hence, LNP-mRNA treatment for fibrosis can restore pulmonary structure and function to similar degrees to those of a healthy lung. This therapy is a potential treatment for IPF patients.

PMID:40258811 | DOI:10.1038/s41467-025-59093-7

Am J Physiol Lung Cell Mol Physiol. 2025 Apr 21. doi: 10.1152/ajplung.00039.2025. Online ahead of print.

ABSTRACT

Type 2 inflammation and epithelial-to-mesenchymal transitions (EMTs) play critical roles in airway repair after damage from allergens or parasites. The matricellular protein periostin (POSTN) has increased expression in inflammatory conditions and has been implicated in fibrosis and EMT, suggesting a role in airway repair. This study investigates the role of periostin in airway epithelial and lung fibroblast wound repair using an in vitro wound model. Our results demonstrate that the type 2 cytokine IL-13 induces periostin secretion from primary human airway epithelial basal cells. Periostin knockdown in human airway epithelial cells (HAEs) and human lung fibroblasts (HLFs) impairs wound closure, indicating that periostin is required for airway repair. In a coculture model of HAE and HLFs, fibroblast-secreted POSTN is required for airway epithelial wound repair, suggesting that periostin is involved in paracrine signaling between the two cell types. These findings highlight periostin's critical function in epithelial and fibroblast-mediated wound repair, suggesting its potential as a therapeutic target for diseases characterized by aberrant wound healing and fibrosis, such as asthma and idiopathic pulmonary fibrosis.

PMID:40257107 | DOI:10.1152/ajplung.00039.2025

Breathe (Sheff). 2025 Apr 17;21(2):240260. doi: 10.1183/20734735.0260-2024. eCollection 2025 Apr.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with limited treatment options. Despite the approval of pirfenidone and nintedanib that slow disease progression, IPF remains a disease with poor survival. Promising therapeutic candidates were tested as potential treatments for IPF and while some drugs were successful in phase II clinical trials, their successful transition to positive phase III was unfortunately disappointing. This highlights the "regression to the truth" concept in drug development, whereby positive phase II trial results may simply be a statistical anomaly rather than the result of true efficacy. We examine three pivotal trials of novel IPF therapies, zinpentraxin alfa, ziritaxestat and pamrevlumab, that failed in late-stage clinical development. These failures underscore common pitfalls in IPF drug development, including inadequate phase II sample sizes, reliance on surrogate endpoints like forced vital capacity, and challenges integrating background antifibrotic therapies. Moving forward, innovative approaches like adaptive trial designs, Bayesian statistics and composite endpoints could improve trial robustness. Moreover, platform trials may accelerate drug development by testing multiple therapies simultaneously. Negative trials are not failures but opportunities for learning. By recognising and addressing these challenges, while also embracing novel trial methodologies, we can enhance drug development and improve IPF outcomes.

PMID:40255293 | PMC:PMC12004256 | DOI:10.1183/20734735.0260-2024

Breathe (Sheff). 2025 Apr 17;21(2):240176. doi: 10.1183/20734735.0176-2024. eCollection 2025 Apr.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial fibrosing disease and, despite some well-known risk factors, its cause is still unknown. Cough is experienced by most patients and is commonly chronic and refractory, having a significant impact on quality of life. Its aetiology is complex, combining factors related to interstitial lung disease (ILD) such as an increased sensitivity of cough-sensitive nerves, structural lung changes and inflammation, genetic factors, several comorbidities and medication-adverse effects. Despite the therapeutic advancements in IPF over the past decade with the introduction of antifibrotic drugs that slow disease progression, effective treatment options for cough in IPF remain unavailable. Cough management often relies on empirical approaches based on studies involving chronic cough patients of unspecified causes and ILD physicians' personal experiences. Different classes of medications have been tried over time and, more recently, the focus has turned to neuromodulators and opioids, but several studies have shown suboptimal efficacy in cough. On the other hand, these drugs are associated with significant physical, psychological and economic burdens. However, the future brings us hope to the extent that most current ongoing clinical trials are using new molecules and some have demonstrated promising antitussive effects. This review aims to provide a practical guide to understanding and managing cough in IPF patients, presenting pharmacological and non-pharmacological approaches over time, as well as those treatments that are currently being investigated in clinical settings.

PMID:40255292 | PMC:PMC12004257 | DOI:10.1183/20734735.0176-2024

Breathe (Sheff). 2025 Apr 17;21(2):240167. doi: 10.1183/20734735.0167-2024. eCollection 2025 Apr.

ABSTRACT

Interstitial lung disease (ILD) is a heterogeneous chronic form of lung disease. The pathogenesis of ILD is poorly understood and a common form of ILD, idiopathic pulmonary fibrosis (IPF) is associated with poor prognosis. There is evidence for substantial dysregulated immune responses in ILD. The microbiome is a key regulator of the immune response, and the lung microbiome correlates with alveolar immunity and clinical outcomes in ILD. Most observational lung microbiome studies have been conducted in patients with IPF. A consistent observation in these studies is that the bacterial burden of the lung is elevated in patients with IPF and predicts mortality. However, our understanding of the mechanism is incomplete and our understanding of the role of the lung microbiome in other forms of ILD is limited. The microbiomes of the oropharynx and gut may have implications for the lung microbiome and pulmonary immunity in ILD but require substantial further research. Here, we discuss the studies supporting a role for the lung microbiome in the pathogenesis of IPF, and briefly describe the putative role of the oral-lung axis and the gut-lung axis in ILD.

PMID:40255291 | PMC:PMC12004254 | DOI:10.1183/20734735.0167-2024

Stem Cell Res Ther. 2025 Apr 20;16(1):194. doi: 10.1186/s13287-025-04313-6.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disorder, presenting clinically with symptoms such as shortness of breath and hypoxemia. Despite its severe prognosis and limited treatment options, the pathogenesis of idiopathic pulmonary fibrosis remains poorly understood. This study aims to investigate the therapeutic potential of mesenchymal stromal cells in treating idiopathic pulmonary fibrosis, focusing on their ability to modulate regulatory T cells through the low tumor necrosis factor superfamily member 4 (TNFSF4) pathway. The goal is to identify mesenchymal stromal cells subtypes with optimal immunomodulatory effects to enhance regulatory T cells functions and ameliorate fibrosis.

METHODS: We identified the immune characteristics of idiopathic pulmonary fibrosis by mining and analyzing multiple public datasets and detecting regulatory T cells in the blood and lung tissues of idiopathic pulmonary fibrosis patients. An extensive examination followed, including assessing the impact of mesenchymal stromal cells on regulatory T cells proportions in peripheral blood and lung tissue, and exploring the specific role of TNFSF4 expression in regulatory T cells modulation. Whole-genome sequencing and cluster analysis were used to identify mesenchymal stromal cells subtypes with low TNFSF4 expression.

RESULTS: Mesenchymal stromal cells characterized by TNFSF4 expression (TNFSF4low-MSCs) demonstrated enhanced ability to regulate regulatory T cells subpopulations and exhibited pronounced anti-fibrotic effects in the bleomycin-induced idiopathic pulmonary fibrosis mouse model. These mesenchymal stromal cells increased regulatory T cells proportions, reduced lung fibrosis, and improved survival rates. TNFSF4-tumor necrosis factor receptor superfamily member 4 (TNFRSF4) signaling was identified as a critical pathway influencing regulatory T cells generation and function.

CONCLUSIONS: Our findings underscore the pivotal role of TNFSF4 in mesenchymal stromal cells mediated regulatory T cells modulation and highlight the therapeutic potential of selecting mesenchymal stromal cells subtypes based on their TNFSF4 expression for treating idiopathic pulmonary fibrosis. This approach may offer a novel avenue for the development of targeted therapies aimed at modulating immune responses and ameliorating fibrosis in idiopathic pulmonary fibrosis.

TRIAL REGISTRATION: Our study involved collecting 10 mL of peripheral blood from idiopathic pulmonary fibrosis patients, and the Medical Ethics Committee of Nanjing Drum Tower Hospital approved our study protocol with the approval number 2023-675-01.

PMID:40254578 | DOI:10.1186/s13287-025-04313-6

J Ethnopharmacol. 2025 Apr 19:119763. doi: 10.1016/j.jep.2025.119763. Online ahead of print.

NO ABSTRACT

PMID:40254530 | DOI:10.1016/j.jep.2025.119763

Respir Investig. 2025 Apr 17;63(4):481-487. doi: 10.1016/j.resinv.2025.04.008. Online ahead of print.

ABSTRACT

BACKGROUND: The Japanese government operates a medical subsidy system for intractable diseases, including idiopathic pulmonary fibrosis (IPF). Registering with this system requires filling out a clinical survey form, which encompasses multiple survey items regarding the patient's disease and functional status. In this study, we retrospectively analyzed the forms of new applicants with IPF in 2019 to evaluate the clinical and functional characteristics.

METHODS: The following patient data were collected: sex, age, smoking status, history of surgical lung biopsy, disease severity (using Japanese severity classification [JSC]), serum biomarkers, findings on chest high-resolution computed tomography (HRCT), functional status, symptoms, and treatment.

RESULTS: Of the 4796 patients reviewed (76.1 % males; mean age = 73.4 ± 8.1 years), 23.6 % had a mild disease (JSC stages I-II) and 76.4 % had a severe disease (stages III-IV). The HRCT of most patients revealed honeycombing, traction bronchiectasis and/or bronchiolectasis, reticular shadows, and subpleural shadows. The positivity rates for elevated serum levels of Krebs von Lungen-6 (KL-6) and surfactant protein-D (SP-D) were 92.6 % and 89.3 %, respectively. As the severity increased, the biomarker positivity rate increased. Approximately half of the patients with milder diseases experienced transportation challenges, and 30 % complained of pain and/or discomfort and anxiety and/or depression.

CONCLUSIONS: In approximately 90 % of patients, serum KL-6 and SP-D levels increased and the positive rate increased as the disease severity increased. Even patients with mild diseases experience challenges in transportation as well as pain, discomfort, anxiety, or depression.

PMID:40250140 | DOI:10.1016/j.resinv.2025.04.008

Front Immunol. 2025 Mar 31;16:1549277. doi: 10.3389/fimmu.2025.1549277. eCollection 2025.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease characterized by abnormal epithelial repair, persistent inflammation, and excessive extracellular matrix deposition, leading to irreversible scarring and respiratory failure. Central to its pathogenesis is the dysregulation of the PI3K/Akt signaling pathway, which drives fibroblast activation, epithelial-mesenchymal transition, apoptosis resistance, and cellular senescence. Senescent cells contribute to fibrosis through the secretion of pro-inflammatory and profibrotic factors in the senescence-associated secretory phenotype (SASP). Current antifibrotic therapies, Nintedanib and Pirfenidone, only slow disease progression and are limited by side effects, highlighting the need for novel treatments. This review focuses on the role of PI3K/Akt signaling in IPF pathogenesis, its intersection with inflammation and fibrosis, and emerging therapeutic approaches targeting molecules along this pathway.

PMID:40248697 | PMC:PMC12004373 | DOI:10.3389/fimmu.2025.1549277

ERJ Open Res. 2025 Apr 14;11(2):00978-2024. doi: 10.1183/23120541.00978-2024. eCollection 2025 Mar.

ABSTRACT

BACKGROUND: A shared genetic component between coronavirus disease 2019 (COVID-19) and idiopathic pulmonary fibrosis (IPF) has been described based on analyses of individual risk variants. Here we used a whole-genome polygenic risk score (PRS) approach to further evaluate age- and sex-stratified genetic overlap between IPF and severe COVID-19 to give insight into shared biological mechanisms that might both inform therapeutic strategies for both diseases.

METHODS: We used results from the largest genome-wide association study of clinically defined IPF risk (4125 cases/20 464 controls) and individual-level data from the SCOURGE European study of COVID-19 (5968 cases/9056 controls). We calculated IPF PRSs and assessed their association with COVID-19 severity, stratified by age and sex. We performed replication in an independent dataset of Latin-American patients (1625 cases/1887 controls). Enrichment and pathway-specific PRS analyses were performed to study biological pathways associated with COVID-19 severity.

RESULTS: IPF PRSs were significantly associated with COVID-19 hospitalisation and severe illness in Europeans and replicated in a Latin-American cohort. The strongest association was found in <60 years patients, especially among younger males (p=6.39×10-5). Pathway-specific PRSs analyses supported a link to cadherin and integrin signalling pathways.

CONCLUSIONS: The study indicates age and sex-dependent genome-wide genetic overlap between IPF and severe COVID-19 and highlights specific shared biological mechanisms underlying both conditions. This could also imply that individuals with a high IPF genetic risk are at an overall increased risk of developing lung sequelae resulting from severe COVID-19.

PMID:40247961 | PMC:PMC12004260 | DOI:10.1183/23120541.00978-2024

AAPS PharmSciTech. 2025 Apr 17;26(5):112. doi: 10.1208/s12249-025-03089-5.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown cause, with few effective therapies available and high mortality rates. Our preceding research indicated that formononetin (FMN) could improve the symptoms of the bleomycin-induced pulmonary fibrosis and be a promising drug against IPF. In this study, an inhalable formononetin-loaded poly(lactic-co-glycolic) acid (PLGA) large porous microspheres (FMN-PLGA-MSs) was prepared by the method of emulsion solvent evaporation. SEM showed that FMN-PLGA-MSs were loose particles existing many pores on the surfaces, and the measured mean geometric diameter was more than 10 µm. The encapsulation efficiency (EE) and drug loading efficiency (DL) were 87.72 ± 6.34% and 4.18 ± 0.30%. FMN in FMN-PLGA-MSs could be rapidly released within 2 h and sustainably released for 21 d. Cell tests and q-RT-PCR tests showed that FMN could inhibit the activation of fibroblasts and the deposition of extracellular matrix (ECM) by acting on the TGF-β1/Smad3 signaling pathway. FMN-PLGA-MSs showed higher antifibrotic effects than free FMN oral administration in the pulmonary fibrosis models of mice, remarkably improving pulmonary function, decreasing hydroxyproline levels, and attenuating lung injuries. By formulating formononetin into microsphere preparations, its solubility can be significantly enhanced, enabling effective pulmonary drug delivery. This approach not only improves lung targeting but also reduces systemic toxicity. Additionally, it facilitates superior lung deposition and extends the retention time of the formononetin within the lungs. Taken together, FMN-PLGA-MSs may be a promising inhaled medication for the treatment of IPF.

PMID:40246731 | DOI:10.1208/s12249-025-03089-5

Rheum Dis Clin North Am. 2025 May;51(2):201-212. doi: 10.1016/j.rdc.2025.01.003. Epub 2025 Feb 28.

ABSTRACT

The lung microbiome is a diverse mucosal environment that has been shown to be implicated in the pathogenesis of various chronic lung diseases including insterstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF). ILD is a well-established manifestation of several types of autoimmune diseases. This review will highlight recent work exploring the role of the lung microbiome in the pathogenesis of autoimmune-related ILD.

PMID:40246438 | DOI:10.1016/j.rdc.2025.01.003

Sci Rep. 2025 Apr 16;15(1):13188. doi: 10.1038/s41598-025-97374-9.

ABSTRACT

Jin Bei oral liquid (JBOL) is a Chinese medicinal preparation for the treatment of idiopathic pulmonary fibrosis (IPF), Clinical trials have shown that IPF patients using JBOL have improved their lung function indicators FVC% and DLCO% by approximately 2.10% and 7.74%, suggesting that the agent has a positive effect in slowing disease progression. In this study, the active volatile components of JBOL were systematically identified and analyzed using gas chromatography-mass spectrometry (GC-MS), network pharmacology and molecular docking techniques. It was found that JBOL contains a variety of compounds with antifibrotic potential, which act through multi-target and multi-pathway mechanisms. Network pharmacological analyses revealed multiple targets of JBOL associated with key pathological processes in IPF, and key active ingredients were screened based on degree values (including Sedanolide, Ligustilide, Senkyunolide H, Senkyunolide I, α-Terpineol, and 4-Terpineol). Molecular docking results showed that these compounds have high affinity for target proteins. Finally, suitable quantitative methods were established and methodologically validated for these six compounds, and these methods were used to determine the content of 8 batches of JBOL and analyze the differences in content between batches.The present study provides a scientific basis for the quality control and standardization of its JBOL by identifying and analyzing its active volatile components.

PMID:40240792 | DOI:10.1038/s41598-025-97374-9

Toxicol Appl Pharmacol. 2025 Apr 14:117342. doi: 10.1016/j.taap.2025.117342. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive extracellular matrix deposition, leading to irreversible lung scarring. This study explores the underlying molecular mechanisms of IPF and delves into membrane-anchored synergism between EGFR and AnxA2, which amplifies fibrotic stress and plays a pivotal role in promoting pulmonary fibroblast activation and fibrosis. Indeed, these interactions create a synergistic effect that promotes the loss of epithelial traits and the transition to a mesenchymal phenotype, thereby contributing to fibrotic stress and disease progression. In addition, this study also explores the potential of butyrate, a short-chain fatty acid, as a therapeutic agent in reducing fibrotic stress by modulating AnxA2-EGFR signaling. Pre-treatment with butyrate significantly dampens AnxA2-EGFR signaling and Galectin-3 expression, effectively curbing prolonged EGFR phosphorylation. The suppression of upstream signaling leads to a reduction in the angiogenic marker VEGF and a decrease in pro-inflammatory mediators such as TNF-α and IL-6. Collectively, our findings highlight the critical role of EGFR-AnxA2 signaling and Galectin 3 in the pathogenesis of IPF, and highlight butyrate as a potential therapeutic agent for alleviating fibrotic stress.

PMID:40239744 | DOI:10.1016/j.taap.2025.117342

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