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

ABSTRACT

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

PMID:40119620 | DOI:10.1002/advs.202405434

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

ABSTRACT

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

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

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

ABSTRACT

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

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

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

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

PMID:40117382 | DOI:10.1093/cei/uxaf019

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

ABSTRACT

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

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

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

ABSTRACT

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

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

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

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

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

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

ABSTRACT

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

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

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

ABSTRACT

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

PMID:40112179 | DOI:10.1002/advs.202415007

Am J Physiol Cell Physiol. 2025 Mar 20. doi: 10.1152/ajpcell.00374.2024. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and degenerative interstitial lung disease characterized by complex etiology, unclear pathogenesis, and high mortality. Long non-coding RNAs (lncRNAs) have been identified as key regulators in modulating the initiation, maintenance, and progression of pulmonary fibrosis. However, the precise pathological mechanisms through which lncRNAs are involved in IPF remain limited and require further elucidation. A novel lncABCE1-5 was identified as significantly decreased by an ncRNA microarray analysis in our eight IPF lung samples compared with three donor tissues and validated by qRT-PCR analysis in clinical lung samples. To investigate the biological function of ABCE1-5, we performed loss-and gain-of-function experiments in vitro and in vivo. LncABCE1-5 silencing promoted A549 cell migration and A549 and BEAS-2B cell apoptosis, while enhancing the expression of proteins associated with extracellular matrix deposition, whereas overexpression of ABCE1-5 partially attenuated TGF-β-induced fibrogenesis. Forced ABCE1-5 expression by intratracheal injection of adeno-associated virus 6 (AAV6) revealing the anti-fibrotic effect of ABCE1-5 in BLM-treated mice. Mechanistically, RNA pull-down-mass spectrometry and RIP assay demonstrated that ABCE1-5 directly binds to keratin14 (krt14) sequences, potentially impeding its expression by perturbing mRNA stability. Furthermore, decreased ABCE1-5 levels can promote krt14 expression and enhance the phosphorylation of both mTOR and Akt; overexpression of ABCE1-5 in BLM mouse lung tissue significantly attenuated the elevated levels of p-mTOR and p-AKT. Knockdown of krt14 reversed the activation of mTOR signaling mediated by ABCE1-5 silencing. Collectively, the downregulation of ABCE1-5 mediated krt14 activation, thereby activating mTOR/AKT signaling, to facilitate pulmonary fibrosis progression in IPF.

PMID:40111939 | DOI:10.1152/ajpcell.00374.2024

Med Phys. 2025 Mar 20. doi: 10.1002/mp.17752. Online ahead of print.

ABSTRACT

BACKGROUND: Deep learning (DL)-based systems have not yet been broadly implemented in clinical practice, in part due to unknown robustness across multiple imaging protocols.

PURPOSE: To this end, we aim to evaluate the performance of several previously developed DL-based models, which were trained to distinguish idiopathic pulmonary fibrosis (IPF) from non-IPF among interstitial lung disease (ILD) patients, under standardized reference CT imaging protocols. In this study, we utilized CT scans from non-IPF ILD subjects, acquired using various imaging protocols, to assess the model performance.

METHODS: Three DL-based models, including one 2D and two 3D models, have been previously developed to classify ILD patients into IPF or non-IPF based on chest CT scans. These models were trained on CT image data from 389 IPF and 700 non-IPF ILD patients, retrospectively, obtained from five multicenter studies. For some patients, multiple CT scans were acquired (e.g., one at inhalation and one at exhalation) and/or reconstructed (e.g., thin slice and/or thick slice). Thus, for each patient, one CT image dataset was selected to be used in the construction of the classification model, so the parameters of that data set serve as the reference conditions. In one non-IPF ILD study, due to its specific study protocol, many patients had multiple CT image data sets that were acquired under both prone and supine positions and/or reconstructed under different imaging parameters. Therefore, to assess the robustness of the previously developed models under different (e.g., non-reference) imaging protocols, we identified 343 subjects from this study who had CT data from both the reference condition (used in model construction) and non-reference conditions (e.g., evaluation conditions), which we used in this model evaluation analysis. We reported the specificities from three model under the non-reference conditions. Generalized linear mixed effects model (GLMM) was utilized to identify the significant CT technical and clinical parameters that were associated with getting inconsistent diagnostic results between reference and evaluation conditions. Selected parameters include effective tube current-time product (known as "effective mAs"), reconstruction kernels, slice thickness, patient orientation (prone or supine), CT scanner model, and clinical diagnosis. Limitations include the retrospective nature of this study.

RESULTS: For all three DL models, the overall specificity of the previously trained IPF diagnosis model decreased (p < 0.05 for two out of three models). GLMM further suggests that for at least one out of three models, mean effective mAs across the scan is the key factor that leads to the decrease in model predictive performance (p < 0.001); the difference of mean effective mAs between the reference and evaluation conditions (p = 0.03) and slice thickness (3 mm; p = 0.03) are flagged as significant factors for one out of three models; other factors are not statistically significant (p > 0.05).

CONCLUSION: Preliminary findings demonstrated the lack of robustness of IPF diagnosis model when the DL-based model is applied to CT series collected under different imaging protocols, which indicated that care should be taken as to the acquisition and reconstruction conditions used when developing and deploying DL models into clinical practice.

PMID:40111345 | DOI:10.1002/mp.17752

Aging Biol. 2024;2:e20240023. doi: 10.59368/agingbio.20240023. Epub 2024 Feb 13.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-associated lung disease of unknown etiology that is characterized by exaggerated deposition of extracellular matrix (ECM), leading to distorted lung architecture, respiratory failure, and death. There are no truly effective treatment options for IPF, thus highlighting the importance of exploring new pathogenic mechanisms that underlie the development of fibrosis and of identifying new therapeutic targets. Insulin-like growth factors (IGFs) are known to be pro-fibrotic. However, the ubiquity and essentiality of IGF receptor signaling in normal physiology limit its potential as a direct therapeutic target. In a recent study, we found a highly significant correlation between expression of pregnancy-associated plasma protein (PAPP)-A in human IPF lung tissue and disease severity. PAPP-A is a unique metalloprotease that enhances local IGF action. In vitro studies support a role for proteolytically active PAPP-A in promoting a fibrotic phenotype in adult human lung fibroblasts. Here, we show that PAPP-A is preferentially expressed in mouse lung fibroblasts and that inhibition of PAPP-A in vivo through PAPP-A gene deletion or a specific neutralizing monoclonal antibody against PAPP-A markedly reduced the progression of bleomycin-induced lung fibrosis, as measured by significantly decreased ECM expression and improved lung histology. Surrogate markers of local IGF receptor activity in the lung were also significantly reduced, indicating indirect modulation of IGF signaling through PAPP-A. These results establish a role for PAPP-A in pulmonary fibrosis and point to PAPP-A as a selective and pharmacologically tractable target for IPF and possibly other fibrotic disorders.

PMID:40110162 | PMC:PMC11922547 | DOI:10.59368/agingbio.20240023

Front Pharmacol. 2025 Mar 5;16:1524505. doi: 10.3389/fphar.2025.1524505. eCollection 2025.

ABSTRACT

OBJECTIVE: This systematic review and meta-analysis aims to assess the efficacy of GBE in the treatment of IPF by evaluating its impact on total effective rate, blood gas analysis, pulmonary function tests, and markers of inflammation and fibrosis.

METHODS: We conducted a comprehensive search across seven databases, including PubMed, EMBASE, Web of Science, CNKI, Wanfang DATA, VIP, and CBM, without restrictions on publication date. Randomized controlled trials (RCTs) that investigated the effects of GBE on IPF patients were eligible for inclusion. Relevant literature was screened, and the data in the included studies were extracted for quality assessment according to the Risk of bias tool.

RESULTS: A total of 14 RCTs involving 1043 patients were included in the analysis. GBE significantly improved the total effective rate, arterial oxygen partial pressure, arterial oxygen saturation, forced vital capacity, forced expiratory volume in one second, maximum voluntary ventilation, and 6-min walk test compared to the control group. Additionally, there was a significant reduction in arterial carbon dioxide partial pressure, interleukin-4, hyaluronan, and laminin levels.

CONCLUSION: GBE may offer therapeutic benefits in IPF by improving respiratory function, modulating inflammation, and affecting fibrosis markers. These findings support the potential use of GBE as an adjunct therapy in IPF and suggest that further large-scale, multicenter trials are warranted to confirm its efficacy and safety.

PMID:40110130 | PMC:PMC11919911 | DOI:10.3389/fphar.2025.1524505

Clin Transplant. 2025 Mar;39(3):e70136. doi: 10.1111/ctr.70136.

ABSTRACT

BACKGROUND: Lung transplantation (LT) is a critical option for patients with advanced respiratory diseases, especially interstitial lung diseases (ILD). The GAP score (Gender, Age, Physiology) has shown prognostic value in idiopathic pulmonary fibrosis (IPF), but its utility in other progressive fibrotic diseases and LT candidates is less well-studied.

METHODS: This retrospective study included ILD patients evaluated as LT candidates between January 2017 and December 2023 at a single center. The GAP score was calculated for each patient, and patients were classified into GAP stages I, II, or III. Outcomes evaluated included LT waiting list inclusion, LT performed, death, and active follow-up without waiting list inclusion. The prognostic utility was analyzed using survival analysis, including Cox regression and Kaplan-Meier methods.

RESULTS: Of 413 ILD patients, 119 were included on the LT waiting list. GAP stage III was an independent predictor of transplant-free survival (HR = 2.720; p = 0.011). Patients in stage II showed a transplant-free survival of 51.3% at 2 years, while stage III had 49.2% survival at 1 year. GAP stages significantly predicted transplant outcomes and survival rates (p < 0.001).

CONCLUSION: The GAP score is a reliable prognostic tool for ILD patients being evaluated for LT, aiding in decision-making regarding referral and waiting list inclusion. It may serve as a useful marker for early referral and prioritization.

PMID:40109152 | DOI:10.1111/ctr.70136

Nature. 2025 Mar 19. doi: 10.1038/s41586-025-08727-3. Online ahead of print.

ABSTRACT

Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ1,2. Mouse lungs follow a stereotyped sequence of fibrogenesis-to-resolution after bleomycin injury3, and we reasoned that profiling post-injury histological stages could uncover pro-fibrotic versus anti-fibrotic features with functional value for human fibrosis. Here we quantified spatiotemporally resolved matrix transformations for integration with multi-omic data. First, we charted stepwise trajectories of matrix aberration versus resolution, derived from a high-dimensional set of histological fibre features, that denoted a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally enriched 'ECM-secreting' (Csmd1-expressing) and 'pro-resolving' (Cd248-expressing) fibroblasts at the respective post-injury stages. Visium-based spatial analysis further suggested divergent matrix architectures and spatial-transcriptional neighbourhoods by fibroblast subtype, identifying distinct fibrotic versus non-fibrotic biomolecular milieu. Critically, pro-resolving fibroblast instillation helped to ameliorate fibrosis in vivo. Furthermore, the fibroblast neighbourhood-associated factors SERPINE2 and PI16 functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis at protein level additionally uncovered analogous fibroblast subtypes and neighbourhoods in human disease. Collectively, these findings establish an atlas of pro- and anti-fibrotic factors that underlie lung matrix architecture and implicate fibroblast-associated biological features in modulating fibrotic progression versus resolution.

PMID:40108456 | DOI:10.1038/s41586-025-08727-3

Eur Respir Rev. 2025 Mar 19;34(175):240147. doi: 10.1183/16000617.0147-2024. Print 2025 Jan.

ABSTRACT

Heat shock protein 90 (HSP 90) and its isoforms are a group of homodimeric proteins that regulate several cellular processes, such as the elimination of misfolded proteins, cell development and post-translational modifications of kinase proteins and receptors. Due to its involvement in extracellular matrix (ECM) remodelling, myofibroblast differentiation and apoptosis, HSP 90 has been investigated as a key player in the pathogenesis of lung fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most common and deadly interstitial lung disease, due to the progressive distortion of lung parenchyma related to the overproduction and deposition of altered ECM, driven by transforming growth factor-β (TGF-β) dependent and independent pathways. The inhibition or induction of HSP 90 is associated with a reduced or increased expression of TGF-β receptors, respectively, suggesting a role for HSP 90 as a biomarker and therapeutic target in IPF. Experimental drugs such as geldanamycin and its derivatives 17-AAG (17-N-allylamino-17-demethoxygeldanamicin) and 17-DMAG (17-dimethylaminoethylamino-17-demethoxigeldanamycin), along with AUY-922, 1G6-D7, AT-13387, TAS-116 and myricetin, have been found to reduce lung fibrosis in both in vivo and in vitro models, supporting the role of this emerging target. This review aims to illustrate the structure and biological function of HSP 90 in the context of IPF pathobiology, as well as perspective application of this molecule as a biomarker and therapeutic target for IPF.

PMID:40107664 | DOI:10.1183/16000617.0147-2024

Eur Respir Rev. 2025 Mar 19;34(175):240238. doi: 10.1183/16000617.0238-2024. Print 2025 Jan.

ABSTRACT

BACKGROUND: Comorbidities can affect drug tolerability and health outcomes in patients with fibrotic interstitial lung disease. This systematic review and meta-analysis evaluated the types and prevalence of comorbidities amongst participants in pharmaceutical randomised controlled trials (RCTs) of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF).

METHODS: Ovid Medline, Embase and CENTRAL databases were searched to identify phase II and III pharmaceutical RCTs of IPF or PPF. Reporting of comorbidities was evaluated, with meta-analyses being performed for the prevalence of different conditions.

RESULTS: 34 articles were included, with 23 unique trials for IPF and one for PPF. A mean of 14 (range 1-44) comorbidities per study was reported in the IPF RCTs, with 11 being reported in the PPF RCT. Common comorbidities in the IPF RCT cohorts were systemic hypertension (pooled prevalence 45%, 95% CI 39-50%), hyperlipidaemia (38%, 95% CI 27-49%), gastro-oesophageal reflux disease (45%, 95% CI 36-54%), ischaemic heart disease (18%, 95% CI 13-42%) and diabetes mellitus (16%, 95% CI 13-20%). The PPF trial cohort had similar types and prevalence of comorbidities to those reported in the IPF trial cohorts.

CONCLUSIONS: Reporting of comorbidities varied across previous IPF RCTs, with limited data available for PPF. Prevalence of comorbidities reported in the IPF and PPF trial cohorts appear to be lower than those reported in prospective patient registries. There is a need for careful consideration of trial eligibility criteria with detailed reporting of comorbidities in future pharmaceutical RCTs to better understand the applicability of trial findings to real-world patients.

PMID:40107663 | DOI:10.1183/16000617.0238-2024

Respir Investig. 2025 Mar 18;63(3):394-398. doi: 10.1016/j.resinv.2025.03.006. Online ahead of print.

ABSTRACT

Both serum and bronchoalveolar lavage fluid levels of galectin-3 (Gal-3) are elevated in patients with idiopathic pulmonary fibrosis (IPF). Phase II study on inhaler with Gal-3 inhibitor for IPF has been ongoing. In this study, 30 treatment-naive patients of IPF were prospectively enrolled and their sera were stored before and after nintedanib treatment. Though Gal-3 levels tended to increase after nintedanib treatment, in some patients, Gal-3 levels decreased immediately after the treatment. Patients whose serum Gal-3 levels decreased 1 month after nintedanib treatment tended to experience a smaller annual decline in forced vital capacity (FVC) than patients with increased Gal-3 levels. Furthermore, the rate of change in Gal-3 levels 1 month after nintedanib treatment positively correlated with the rate of annual FVC decline, whereas that of other fibrotic markers did not correlate with the rate of annual FVC decline. This study suggested that a decline in serum Gal-3 levels immediately after nintedanib treatment may predict less progression of IPF treated with nintedanib.

PMID:40107223 | DOI:10.1016/j.resinv.2025.03.006

Respir Med Case Rep. 2025 Feb 27;54:102184. doi: 10.1016/j.rmcr.2025.102184. eCollection 2025.

ABSTRACT

An 81-year-old man with a history of interstitial lung disease attributed to idiopathic pulmonary fibrosis, severe aortic stenosis, and stable coronary artery disease was started on inhaled treprostinil for pulmonary hypertension associated with interstitial lung disease to optimize hemodynamics prior to the valve replacement procedure. However, two days after starting this treatment, the patient presented with an inferior-posterior ST elevation myocardial infarction. Urgent coronary angiography revealed a 95 % proximal right coronary artery stenosis, successfully treated with percutaneous coronary intervention and drug-eluting stent placement. This case raises a question of whether there could be a potential association between inhaled treprostinil initiation and acute myocardial infarction in patients with underlying coronary artery disease. With the documented stability of the patient's coronary artery disease prior to medication initiation, it is plausible to question whether treprostinil may have played a role in plaque destabilization.

PMID:40104432 | PMC:PMC11915154 | DOI:10.1016/j.rmcr.2025.102184

Nat Rev Drug Discov. 2025 Mar 18. doi: 10.1038/s41573-025-01158-9. Online ahead of print.

ABSTRACT

Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.

PMID:40102636 | DOI:10.1038/s41573-025-01158-9

Respir Investig. 2025 Mar 17;63(3):365-372. doi: 10.1016/j.resinv.2025.02.009. Online ahead of print.

ABSTRACT

BACKGROUND: Prognostic factors in patients with newly diagnosed idiopathic interstitial pneumonia (IIP) have rarely been analyzed using prospective data. This study investigated prognostic factors in patients with IIP.

METHODS: Central interstitial lung disease (ILD) experts established the diagnoses for fibrotic ILD. Prognostic factors using baseline data, including the pathological confidence level of usual interstitial pneumonia (UIP) assessed on a 0%-100% linear analog scale by high-resolution CT (HRCT), pulmonary function tests, and patient-reported outcomes were investigated.

RESULTS: Overall, 866 eligible patients were registered. Patients with unclassifiable idiopathic interstitial pneumonia (n = 272) survived longer than those with idiopathic pulmonary fibrosis (IPF) (n = 469) (hazard ratio [HR] = 0.67; [95% confidence interval [CI]: 0.47-0.95]; P = 0.022); however, IPF as IIPs classification was not a significant prognostic factor at diagnosis (P = 0.577). UIP pattern on HRCT, age, body mass index, forced vital capacity, diffusing capacity of the lungs for carbon monoxide, and St. George's Respiratory Questionnaire were risk factors for survival (P < 0.05). Patients with proposed progressive pulmonary fibrosis (PPF) had poorer prognoses than those without proposed PPF (HR = 5.63; [95% CI: 3.17-10.00]; P < 0.001). Patients with progressive fibrosing ILD (PF-ILD) had poorer prognoses than those without PF-ILD (HR = 7.85; [95% CI: 3.38-18.3]; P < 0.001).

CONCLUSIONS: A prospective registry of patients with newly diagnosed IIP provided evidence that the UIP pattern on HRCT by analog scale was a prognostic predictor. Proposed PPF and PF-ILD were valuable for discriminating prognosis. (JIPS Registry, ClinTrials.gov, NCT03041623).

PMID:40101437 | DOI:10.1016/j.resinv.2025.02.009

J Clin Invest. 2025 Mar 18:e181775. doi: 10.1172/JCI181775. Online ahead of print.

ABSTRACT

Tissue regenerative responses involve complex interactions between resident structural and immune cells. Recent reports indicate that accumulation of senescent cells during injury repair contributes to pathological tissue fibrosis. Using tissue-based spatial transcriptomics and proteomics, we identified upregulation of the immune checkpoint protein, cytotoxic T-lymphocyte associated protein 4 (CTLA4) on CD8+ T cells adjacent to regions of active fibrogenesis in human idiopathic pulmonary fibrosis (IPF) and in a murine model of repetitive bleomycin lung injury model of persistent fibrosis. In humanized CTLA4 knock-in mice, treatment with ipilimumab, an FDA-approved drug that targets CTLA4, resulted in accelerated lung epithelial regeneration and diminished fibrosis from repetitive bleomycin injury. Ipilimumab treatment resulted in the expansion of Cd3e+ T cells, diminished accumulation of senescent cells, and robust expansion of type 2 alveolar epithelial cells, facultative progenitor cells of the alveolar epithelium. Ex-vivo activation of isolated CTLA4-expressing CD8+ cells from mice with established fibrosis resulted in enhanced cytolysis of senescent cells, suggesting that impaired immune-mediated clearance of these cells contribute to persistence of lung fibrosis in this murine model. Our studies support the concept that endogenous immune surveillance of senescent cells may be essential in promoting tissue regenerative responses that facilitate the resolution of fibrosis.

PMID:40100323 | DOI:10.1172/JCI181775