Respiration. 2025 Mar 28:1-10. doi: 10.1159/000545165. Online ahead of print.

ABSTRACT

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease that subverts the normal structure of the lungs and finally causes respiratory failure. High flow nasal therapy (HFNT) is currently used in the acute setting for IPF with acute respiratory failure (ARF). Also, acute exacerbation of IPF (AE-IPF) and end-stage disease are common indications. Chronic cough is often an unmet need in IPF because it is partially responsive to common pharmacological treatment. Moreover, opioids have known adverse events. The aim of this paper is to investigate the effects and safety of chronic HFNT on lung function and symptoms of IPF. Methods This is a single center case-control study including patients affected by IPF. We included 35 adult patients with a consistent radiological diagnosis of IPF, clinical history of lung function decline and high prevalence of symptoms. All patients received the standard of treatment, particularly including antifibrotic drugs and conventional oxygen therapy (COT). 18 subjects were assigned to additional treatment with HFNT for 12 months. Results No significant differences were observed after the follow up with HFNT in terms of lung function. Results are showed in Figure 1. The mean FVC was 1.89 ± 0.73 L with HFNT and 2.43 ± 0.87 without HFNT (p=0.09). The mean FVC % of predicted is shown in Fig.1A; the mean FVC decline per year was 190 with HFNT vs 200 ml with standard of care. The mean DLCO % of predicted was 28.86 ± 14.51 % of predicted with HFNT and 36.03 ± 19.18 with COT (p=0.276), as shown in Fig.1B. No significant impact was observed on dyspnea, the mean borg scale value was 6.72 ± 2.22 after HFNT and 7.14 with COT (p=0.56) (Fig.1C). The score for cough significantly improved after treatment with a mean score in the HFNT group being 46.67 ± 10.85 vs 73.8 ± 18.43 (p<0.0001) with standard of care. Conclusions Long-term HFNT significantly reduces chronic cough in patients affected by IPF compared to COT. Lung function including FVC and DLCO is not significatively influenced.

PMID:40159397 | DOI:10.1159/000545165

Zhonghua Jie He He Hu Xi Za Zhi. 2025 Apr 12;48(4):389-392. doi: 10.3760/cma.j.cn112147-20240806-00465.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic lung disease of unknown etiology, primarily affecting middle-aged and elderly individuals. Chest imaging and histopathology are characterized by usual interstitial pneumonia (UIP). Without treatment, the median survival of patients is 3-5 years. Disease progression or acute exacerbation in IPF patients indicates a poor survival prognosis. Therefore, identification and establishment of predictive models for assessing IPF disease behavior may allow early prediction of disease progression, facilitating timely intervention or adjustment of therapeutic strategies to improve outcomes. This review aimed to summarized recent advances in IPF predictive models and to highlight key issues that need to be addressed.

PMID:40159060 | DOI:10.3760/cma.j.cn112147-20240806-00465

Zhonghua Jie He He Hu Xi Za Zhi. 2025 Apr 12;48(4):358-364. doi: 10.3760/cma.j.cn112147-20241203-00716.

ABSTRACT

Objective: To explore the clinicopathological characteristics and prognosis of lung cancer arising in the native lung after single lung transplantation for end-stage lung disease. Methods: We conducted a respective analysis of the clinical, pathological, and follow-up data of 12 recipients who developed lung cancer in the native lung after single-lung transplantation at China-Japan Friendship Hospital from September 2017 to June 2021, among a total of 247 single-lung transplantations performed during this period. Eleven were male and 1 was female, with ages ranging from 46-67 (59.25±5.75) years. Results: Of the 12 recipients, 11 had a smoking history before transplantation. The underlying diagnosis of lung diseases before transplantation included 8 cases of idiopathic pulmonary fibrosis, 3 cases of connective tissue disease-associated interstitial lung disease, and 1 case of chronic obstructive pulmonary disease. The time interval from transplantation to the development of lung cancer in the native lung was 3 to 53 months, with an average of (30.0±16.2) months. Eleven patients had elevated levels of serum tumor markers at the time of lung cancer diagnosis. CT/PET-CT showed new nodules or FDG avidity in the native lung. The histological types of lung cancer in the 12 cases included 1 case of small cell carcinoma and 11 cases of non-small cell lung cancer (7 cases of squamous cell carcinoma, 3 cases of adenocarcinoma, and 1 case of SMARCA4-deficient undifferentiated carcinoma). There were 8 cases in clinical stage Ⅳ, 1 case in stage Ⅲ, and 3 cases in stageⅠ. Three patients in stage Ⅰ and one patient in stage Ⅲ underwent surgical treatment, while patients in stage Ⅳ were treated with radiotherapy, chemotherapy, and palliative care. At the end of this study, 10 patients had died, 1 patient survived, and 1 patient was lost to follow-up. The median survival time was 7 months (ranging from 2 to 47 months), and the 1-year cumulative survival rate was 9.2%. Conclusions: The risk of developing lung cancer in the native lung after single lung transplantation is increased. The prognosis is very poor. Most of the histological types are squamous cell carcinoma. Close monitoring of high-risk populations after transplantation for early tumor detection may prolong survival time.

PMID:40159054 | DOI:10.3760/cma.j.cn112147-20241203-00716

Eur Respir J. 2025 Mar 28:2402249. doi: 10.1183/13993003.02249-2024. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with severe COVID-19 may develop lung fibrosis. Pirfenidone is an anti-fibrotic drug approved for idiopathic pulmonary fibrosis. The efficacy and safety of pirfenidone in patients with fibrotic interstitial lung changes after recovery from severe COVID-19 pneumonia was evaluated.

METHODS: Phase 2, double-blind, placebo-controlled, Spanish multicenter clinical trial randomized to receive pirfenidone or placebo (2:1) for 24-weeks. The primary endpoint was the proportion of patients that improved, considered when percent change in forced vital capacity (FVC) was ≥10% and/or any reduction in the fibrotic score chest high-resolution computed tomography (HRCT). Secondary endpoints included health-related quality of life (HRQoL), exercise capacity, and drug safety profile.

RESULTS: From 119 eligible patients, 113 were randomized and 103 were analyzed (pirfenidone n=69, placebo n=34). Most patients were male (73.5%) and were receiving low-dose prednisone; mean age was 63.7 years and body-mass index was 29 kg·m-2. The percentage of patients that improved was similar in the pirfenidone and placebo groups (79.7% versus 82.3%, respectively). The mean predicted FVC (%) increased 12.74 (20.6) with pirfenidone and 4.35 (22.3) with placebo (p=0.071), and the HRCT (%) fibrotic score reduced 5.44 (3.69) with pirfenidone and 2.57 (2.59) with placebo (p=0.52). Clinically meaningful improvement in HRQoL was not statistically different (55.2% in pirfenidone and 39.4% in placebo group, respectively). Exercise capacity, adverse events and hospitalizations were similar between groups. No deaths were reported.

CONCLUSIONS: The overall improvement in lung function and the HRCT fibrotic score after 6 months with pirfenidone was not significantly different than placebo.

PMID:40154560 | DOI:10.1183/13993003.02249-2024

Am J Respir Crit Care Med. 2025 Mar 28. doi: 10.1164/rccm.202410-1934OC. Online ahead of print.

ABSTRACT

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of type 1 collagen. 68Ga-CBP8, a type 1 collagen positron emission tomography (PET) probe, measures collagen accumulation and shows higher collagen deposition in patients with IPF. Bexotegrast (PLN-74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under late-stage evaluation for treatment of IPF. Objectives: Evaluate changes in type 1 collagen in the lungs of participants with IPF following treatment with bexotegrast. Methods: In this Phase 2 (NCT05621252), single-center, double-blind, placebo-controlled study, adults with IPF received bexotegrast 160mg or placebo for 12 weeks. Primary endpoint was the change in whole-lung standardized uptake value (SUV) of 68Ga-CBP8 PET. Changes in lung dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters, forced vital capacity (FVC), cough severity, and biomarkers of collagen synthesis and progressive disease were also assessed. Measurements and Main Results: Of 10 participants, 7 received bexotegrast and 3 placebo. At Week 12, mean change from baseline in top quartile of 68Ga-CBP8 whole-lung SUV was -1.2% with bexotegrast vs 6.6% with placebo; greatest mean changes were observed in subpleural lung regions in both groups (bexotegrast, -3.7%; placebo, 10.3%). DCE-MRI demonstrated numerically increased peak enhancement and faster contrast washout rate in bexotegrast-treated participants, suggesting improvements in lung microvasculature and decreased extravascular extracellular volume. Bexotegrast treatment resulted in numerical improvements in FVC, cough severity, and biomarker levels. Conclusions: The reduced uptake of 68Ga-CBP8 in the lungs of participants with IPF indicates an antifibrotic effect of bexotegrast, suggesting the potential for favorable lung remodeling.

PMID:40153543 | DOI:10.1164/rccm.202410-1934OC

Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 28. doi: 10.1007/s00210-025-04076-0. Online ahead of print.

ABSTRACT

The molecular link between endoplasmic reticulum stress (ERS) and idiopathic pulmonary fibrosis (IPF) remains elusive. Our study aimed to uncover core mechanisms and new therapeutic targets for IPF. By analyzing gene expression profiles from the Gene Expression Omnibus (GEO) database, we identified 1519 differentially expressed genes (DEGs) and 11 ERS-related genes (ERSRGs) diagnostic for IPF. Using weighted gene co-expression network analysis (WGCNA) and differential expression analysis, key genes linked to IPF were pinpointed. CIBERSORT was used to assess immune cell infiltration, while the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore biological mechanisms. In three GEO datasets (GSE150910, GSE92592, and GSE124685), the receiver operating characteristic (ROC) curve analysis showed area under the ROC curve (AUC) > 0.7 for all ERSRGs. The Connectivity Map (CMap) database was used to predict small molecules modulating IPF signatures. The molecular docking energies of mirdametinib with protein targets ranged from - 5.1643 to - 8.0154 kcal/mol, while those of linsitinib ranged from - 5.6031 to - 7.902 kcal/mol. Molecular docking and animal experiments were performed to validate the therapeutic potential of identified compounds, with mirdametinib showing specific effects in a murine bleomycin-induced pulmonary fibrosis model. In vitro experiments indicated that mirdametinib may alleviate pulmonary fibrosis by reducing ERS via the PI3K/Akt/mTOR pathway. Our findings highlight 11 ERSRGs as predictors of IPF and demonstrate the feasibility of bioinformatics in drug discovery for IPF treatment.

PMID:40153017 | DOI:10.1007/s00210-025-04076-0

Biomedicines. 2025 Mar 11;13(3):690. doi: 10.3390/biomedicines13030690.

ABSTRACT

Background: Cold exposure has an impact on various respiratory diseases. However, its relationship with idiopathic pulmonary fibrosis (IPF) remains to be elucidated. In this study, bioinformatics methods were utilized to explore the potential link between cold exposure and IPF. Methods: Cold exposure-related genes (CERGs) were identified using RNA-Seq data from mice exposed to cold versus room temperature conditions, along with cross-species orthologous gene conversion. Consensus clustering analysis was performed based on the CERGs. A prognostic model was established using univariate and multivariate risk analyses, as well as Lasso-Cox analysis. Differential analysis, WGCNA, and Lasso-Cox methods were employed to screen for signature genes. Results: This study identified 151 CERGs. Clustering analysis based on these CERGs revealed that IPF patients could be divided into two subgroups with differing severity levels. Significant differences were observed between these two subgroups in terms of hypoxia score, EMT score, GAP score, immune infiltration patterns, and mortality rates. A nine-gene prognostic model for IPF was established based on the CERG (AUC: 1 year: 0.81, 3 years: 0.79, 5 years: 0.91), which outperformed the GAP score (AUC: 1 year: 0.66, 3 years: 0.75, 5 years: 0.72) in prognostic accuracy. IPF patients were classified into high-risk and low-risk groups based on the RiskScore from the prognostic model, with significant differences observed between these groups in hypoxia score, EMT score, GAP score, immune infiltration patterns, and mortality rates. Ultimately, six high-risk signature genes associated with cold exposure in IPF were identified: GASK1B, HRK1, HTRA1, KCNN4, MMP9, and SPP1. Conclusions: This study suggests that cold exposure may be a potential environmental factor contributing to the progression of IPF. The prognostic model built upon cold exposure-related genes provides an effective tool for assessing the severity of IPF patients. Meanwhile, GASK1B, HRK1, HTRA1, KCNN4, MMP9, and SPP1 hold promise as potential biomarkers and therapeutic targets for IPF.

PMID:40149666 | DOI:10.3390/biomedicines13030690

Am J Hosp Palliat Care. 2025 Mar 27:10499091251329920. doi: 10.1177/10499091251329920. Online ahead of print.

ABSTRACT

BackgroundBreathlessness is a distressing and prevalent symptom in fibrotic interstitial lung disease. Dyspnea management requires systematic assessment including patients' lived experiences; however, most dyspnea tools are point-in-time numerical severity scales. The Edmonton Dyspnea Inventory was developed to assess severity at rest, during activities of daily living and self-reported activities. It enables documentation of crisis dyspnea episodes and triggers clinicians to guide action plans and dyspnea management. This study is part of a larger project to validate the tool. The purpose was to describe patient perceptions of assessment of breathlessness of patient use of the tool.MethodsPatients with fibrotic interstitial lung disease were invited to share their perceptions and experiences of breathlessness and the tool. Focus groups were led on Zoom©, with patient-participants in their homes. Data were analysed with inductive content analysis for development of themes.ResultsThirteen patients participated in 2 focus groups. There were 4 major themes, each with minor themes: physicians need to explicitly ask about breathlessness; the tool conveys breathlessness and disease progression; the tool increases self-awareness of breathlessness and complexity; and the tool helps prevent crises and manage breathlessness. Patient-participants perceived the tool provided the needed language and means to focus and relay their breathlessness to others.ConclusionPatient-participants reported the tool was easy to understand and integrate in daily living. They recommended its use for general and specialized practitioners. Developed to assess breathlessness, the tool may provide a framework to promote patient self-awareness, describe individual progression, and tailor breathlessness self-management.

PMID:40147029 | DOI:10.1177/10499091251329920

Am J Physiol Lung Cell Mol Physiol. 2025 Mar 27. doi: 10.1152/ajplung.00286.2024. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis(IPF) is a chronic progressive lung disease that leads to destruction of alveoli and replacement by fibrotic tissue. Metabolic profiling of lung tissue and serum from IPF patients has revealed that levels of tricarboxylic acid (TCA) cycle metabolites such as succinate are altered in patients with IPF. In our study, we aim to evaluate the role of succinate and its receptor- succinate receptor 1 (SUCNR1) in the pathogenesis of lung fibrosis, with a focus on fibroblasts, a central cell in IPF.

METHODS: SUCNR1 expression was investigated using Western blots, qPCR, and FISH. In vitro assays with IPF and normal human lung fibroblasts(NHLF) were used to evaluate the effect of succinate treatment on the expression of fibrotic markers, fibroblast-myofibroblast transition, apoptosis and signaling mechanisms. Studies with the bleomycin mouse model of PF were used to evaluate the effect of succinate in vivo.

RESULTS: Several cell types in the lung express SUCNR1 including ATII cells, fibroblasts, and macrophages. In IPF patient fibroblasts, succinate treatment increased expression of fibrosis associated markers such as alpha smooth muscle actin and collagen. Moreover, succinate exaggerated TGF-β-mediated fibroblast-to-myofibroblast transition in NHLF. In vivo, succinate treatment significantly increased collagen accumulation in the lung and enhanced weight loss in bleomycin-treated mice. Importantly, succinate-mediated elevation of fibrosis-associated markers was lost upon knockdown of SUCNR1 or inhibition of ERK activation in IPF patient-derived fibroblasts.

CONCLUSION: Succinate exerted pro-fibrotic effects in vitro and in vivo. Thus, SUCNR1 antagonism may be a potential therapeutic target for the treatment of IPF.

PMID:40146935 | DOI:10.1152/ajplung.00286.2024

Curr Opin Pulm Med. 2025 Mar 27. doi: 10.1097/MCP.0000000000001169. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: This review examines the current understanding of telomere biology disorders (TBDs) in advanced lung disease, with particular focus on their implications for lung transplantation outcomes and management.

RECENT FINDINGS: Recent studies have revealed that TBDs are enriched in lung transplant populations, with many idiopathic pulmonary fibrosis transplant recipients having short telomeres and/or carrying variants in telomere-related genes. While survival outcomes remain debated, recipients with short telomeres consistently show increased susceptibility to cytopenias, cytomegalovirus (CMV) infection, and may require modified immunosuppression regimens. New evidence suggests potential protection against acute cellular rejection in some cases, and novel approaches using letermovir for CMV prophylaxis show promise in managing these complex patients.

SUMMARY: Management of lung transplant recipients with TBDs requires careful consideration of multiorgan manifestations and individualized management strategies. A multidisciplinary approach incorporating genetics, haematology, and hepatology expertise is increasingly essential for optimal outcomes in this unique population.

PMID:40145203 | DOI:10.1097/MCP.0000000000001169

JHLT Open. 2023 Oct 20;2:100011. doi: 10.1016/j.jhlto.2023.100011. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Acute exacerbations of interstitial lung disease (AE-ILD) cause severe respiratory failure, and mortality is high despite treatment. Lung transplantation is an effective therapy for late-stage interstitial lung disease (ILD), but prior studies on post-transplant outcomes for patients trandsplanted in AE-ILD are conflicting.

METHODS: We performed a retrospective evaluation of all first-time lung transplant recipients for ILD performed at our institution between May 1, 2005, and April 1, 2019. Patients were stratified according to a published consensus definition into AE-ILD recipients, other inpatients, or outpatients. One-year survival was compared with a Cox proportional hazards model. Subset analysis was performed on those with idiopathic pulmonary fibrosis (IPF). Patients were also assessed for survival free of long-term chronic lung allograft dysfunction (CLAD).

RESULTS: We identified 717 first-time lung transplant ILD recipients: 41 inpatients in AE-ILD, 31 other inpatients, and 645 outpatients. One-year survival was 93% for AE-ILD recipients, 61% for other inpatient recipients, and 82% for outpatient recipients. Those transplanted in AE-ILD had a lower hazard of death or retransplantation compared to other inpatients (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.04-0.56) and outpatients (HR 0.29, CI 0.09-1.00). Results were similar among the subset of patients with IPF, but differences were not significant. For those transplanted during AE-ILD, rates of CLAD were not significantly different compared to other inpatients (HR 1.34, CI 0.51-3.54) or to outpatients (HR 1.05, CI 0.52-2.13).

CONCLUSIONS: With careful selection, patients in AE-ILD can be transplanted and have acceptable 1-year outcomes without increased risk of long-term graft dysfunction.

PMID:40144010 | PMC:PMC11935389 | DOI:10.1016/j.jhlto.2023.100011

JHLT Open. 2024 Apr 25;5:100101. doi: 10.1016/j.jhlto.2024.100101. eCollection 2024 Aug.

ABSTRACT

Chimeric antigen receptor T-cell therapy (CAR-T) has been used to treat refractory post-transplant lymphoproliferative disorder (PTLD) in solid organ transplant patients, including heart, kidney, liver, intestine, and pancreas. We report the use of CAR-T for treating refractory PTLD in a 73-year-old female who was 7 years post bilateral lung transplantation for idiopathic pulmonary fibrosis. We discuss the immunosuppression management in this patient, as well as her clinical course and outcome.

PMID:40143897 | PMC:PMC11935479 | DOI:10.1016/j.jhlto.2024.100101

JHLT Open. 2024 Jul 1;5:100122. doi: 10.1016/j.jhlto.2024.100122. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Predicting post-transplant (PT) survival in lung allocation remains an elusive goal. We analyzed the impact of donor factors on PT survival and how these relationships vary among transplant recipients.

METHODS: We studied primary bilateral lung transplant recipients (n = 7,609) from the US Scientific Registry of Transplant Recipients (19 February 2015-1 February 2020). Main and interaction effects were evaluated and adjusted across candidate age, sex, and diagnosis. Models predicting PT survival were compared to the PT Composite Allocation Score model (PT-CAS): (1) Cox regression donor multivariable model (COX), (2) COX + PT-CAS, (3) random forest model (RF), and (4) RF + PT-CAS. Model discrimination and calibration measures were compared.

RESULTS: Interactions between donor and recipient factors emerged by age: lower survival for donation after circulatory death organs for recipients aged 55 to 69 years, donor smoking for recipients aged 30 to 54 and 70+, Hispanic donor for recipients <30, non-Hispanic Black donor for recipients aged 30+; sex: cytomegalovirus mismatch for males; diagnosis: higher donor recipient weight ratio for diagnosis group C (e.g., cystic fibrosis), donor diabetes for diagnosis group D (e.g., idiopathic pulmonary fibrosis). COX and RF models performed similarly to PT-CAS; however, the combined COX + PT-CAS model had improved discrimination (1-year area under the receiver operator characteristic curve [AUC] PT-CAS 0.609 vs 1-year AUC COX + PT-CAS 0.626) and improved calibration across a broader range of predicted risk.

CONCLUSIONS: The influence of donor factors on recipient PT survival differed by age, sex, and diagnosis. The addition of donor factors to existing models predicting PT survival led to only modest improvement in prediction accuracy. Future efforts may focus on optimizing matching strategies to improve donor utilization.

PMID:40143895 | PMC:PMC11935449 | DOI:10.1016/j.jhlto.2024.100122

Pharmaceuticals (Basel). 2025 Mar 14;18(3):411. doi: 10.3390/ph18030411.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown aetiology. Evidence on the progression of idiopathic pulmonary fibrosis (IPF) following the introduction of antifibrotic therapies still indicates a generally poor prognosis. IPF is associated with both respiratory and non-respiratory comorbidities, which can worsen symptoms and impact overall survival. Background/Objectives: The study aimed to investigate the effect of these comorbidities on the early and permanent discontinuation of pirfenidone or nintedanib in IPF patients. Methods: In this single-centre retrospective study, 101 patients diagnosed with IPF according to ATS/ERS/JRS/ALAT guidelines were treated with AFT. Clinical data were collected at 12 months prior to and up to 24 months following treatment initiation, including age, gender, smoking history, and the presence of respiratory and non-respiratory comorbidities. Results: The data showed that 21 patients (20.8%) discontinued treatment within the first 12 months. Additionally, pre-treatment comorbidities were not statistically correlated with the suspension of antifibrotic treatment. Among the overall cohort, 77 patients (76.2%) had at least one comorbidity and 27 (26.7%) had three or more comorbidities. Notably, 24 (23.8%) had respiratory comorbidities, while 75 (74.3%) had non-respiratory comorbidities. Conclusions: This real-life study emphasises the complexities involved in managing IPF, particularly regarding adherence to treatment when significant comorbidities are present. The evidence suggests that in patients with IPF, pre-treatment respiratory or non-respiratory conditions do not affect AFT discontinuation.

PMID:40143187 | DOI:10.3390/ph18030411

Molecules. 2025 Mar 14;30(6):1311. doi: 10.3390/molecules30061311.

ABSTRACT

Silicosis is an interstitial lung disease (ILD) caused by prolonged inhalation of silica particles. Acute lung injury (ALI) is a critical clinical syndrome involving bilateral lung infiltration and acute hypoxic respiratory failure. However, there is currently no effective treatment for these two diseases. Previous research has established that cyclic adenosine monophosphate (cAMP) is pivotal in the pathogenesis of silicosis and acute lung injury. Phosphodiesterase 4 (PDE4) is a hydrolase enzyme of cAMP, and BI 1015550, as an inhibitor of PDE4B, is expected to be a candidate drug for treating both. BI 1015550 has shown certain anti-inflammatory and anti-fibrotic properties in systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF), but there is a lack of research on silicosis and acute lung injury. In this research, we successfully synthesized BI 1015550 autonomously and demonstrated that it could significantly improve lung fibrosis and inflammation in a silica-induced silicosis mouse model. Furthermore, we found that BI 1015550 could also alleviate lung inflammation in a Lipopolysaccharide (LPS)-induced acute lung injury mouse model. The mechanism of action may involve the regulation of cAMP-related signaling pathways.

PMID:40142089 | DOI:10.3390/molecules30061311

Int J Mol Sci. 2025 Mar 19;26(6):2760. doi: 10.3390/ijms26062760.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies.

PMID:40141400 | DOI:10.3390/ijms26062760

Int J Mol Sci. 2025 Mar 17;26(6):2705. doi: 10.3390/ijms26062705.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable chronic interstitial lung disease characterized by excessive fibrosis and impaired lung function. Current treatments, such as pirfenidone and nintedanib, slow disease progression but fail to halt or reverse fibrosis, highlighting the need for novel approaches. Activin A, which belongs to the TGF-β superfamily, is implicated in various fibrosis-related mechanisms, including epithelial-mesenchymal transition (EMT), a process where epithelial cells acquire mesenchymal characteristics, and fibroblast-myofibroblast transformation (FMT), in which fibroblasts differentiate into contractile myofibroblasts. It also promotes inflammatory cytokine release and extracellular matrix buildup. This study aimed to inhibit Activin A activity using synthetic peptides identified through phage display screening. Of the ten peptides isolated, A7, B9, and E10 demonstrated high binding affinity and inhibitory activity. Computational modeling confirmed that these peptides target the receptor-binding domain of Activin A, with peptide E10 exhibiting superior efficacy. Functional assays showed that E10 reduced cell migration, inhibited EMT in A549 cells, and suppressed FMT in fibroblast cultures, even under pro-fibrotic stimulation with TGF-β. These findings underscore the therapeutic potential of targeting Activin A with synthetic peptides, offering a promising avenue for IPF treatment and expanding the arsenal of anti-fibrotic strategies.

PMID:40141346 | DOI:10.3390/ijms26062705

AAPS PharmSciTech. 2025 Mar 26;26(4):94. doi: 10.1208/s12249-025-03086-8.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a rare and serious chronic interstitial lung disease that may endanger the lives of patients. The median survival time of patients with idiopathic pulmonary fibrosis is short, and the mortality rate is higher than that of many types of cancer. At present, pirfenidone (PFD) and nintedanib (NDNB) have been approved by FDA for IPF, but they can only delay the process of pulmonary fibrosis and cannot cure the disease. Therefore, it is urgent to develop other drugs with the effect of improving pulmonary fibrosis. Ellagic acid (EA) can inhibit the Wnt-signaling pathway and has an effect in treating pulmonary fibrosis induced by bleomycin (BLM) in mice. However, its solubility is poor, resulting in its low bioavailability and limited therapeutic benefits, so its clinical application has been limited. Herein, based on the characteristics of nano-drug lung delivery system, chitosan (CS) was selected as the carrier, and ellagic acid-loaded chitosan nanoparticles (EA-CS-NPs) were prepared by ionic gelation method. The EE% and DL% of prepared EA-CS-NPs was 73.73 ± 4.52% and 6.23 ± 1.09%, the particle size was 119.6 ± 5.51 nm (PDI = 0.234 ± 0.017), the zeta potential was 29.833 ± 0.503 mV. The morphology of the nanoparticles was observed by TEM microscope, which was round, uniform dispersion, indicating that the preparation process is stable and feasible. The toxicity experiment showed that EA-CS-NPs maintained 80% cell viability, significantly higher than that of the NDNB group, indicating lower toxicity and better inhibitory effects on TGF-β1-stimulated MLg and NIH-3T3 cells. Wound healing assay results showed that the inhibitory effect of EA-CS-NPs on cell migration was more pronounced than that of EA in the same amount of EA-containing drugs. Drug uptake experiments revealed that EA-CS-NPs significantly enhanced drug uptake in MLg and NIH-3T3 cells. In vivo, Cy7-CS-NPs exhibited higher fluorescence intensity in rat lungs compared to Cy7 solution, indicating better lung retention. The in vivo efficacy test showed that compared with the EA group, EA-CS-NPs could better reduce the area of pulmonary fibrosis and collagen deposition, improve lung function, and have a longer retention time in the lung. In summary, our results revealed that EA-CS-NPs may be a good choice for the treatment of pulmonary fibrosis.

PMID:40140157 | DOI:10.1208/s12249-025-03086-8

Cells. 2025 Mar 7;14(6):394. doi: 10.3390/cells14060394.

ABSTRACT

Pulmonary fibrosis due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the leading cause of death in patients with COVID-19. β-catenin, a key molecule in the Wnt/β-catenin signaling pathway, has been shown to be involved in the development of pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, silicosis). In this study, we developed a SARS-CoV-2-infected A549-hACE2 cell model to evaluate the efficacy of the A549-hACE2 monoclonal cell line against SARS-CoV-2 infection. The A549-hACE2 cells were then subjected to either knockdown or overexpression of the effector β-catenin, and the modified cells were subsequently infected with SARS-CoV-2. Additionally, we employed transcriptomics and raw letter analysis approaches to investigate other potential effects of β-catenin on SARS-CoV-2 infection. We successfully established a model of cellular fibrosis induced by SARS-CoV-2 infection in lung-derived cells. This model can be utilized to investigate the molecular biological mechanisms and cellular signaling pathways associated with virus-induced lung fibrosis. The results of our mechanistic studies indicate that β-catenin plays a significant role in lung fibrosis resulting from SARS-CoV-2 infection. Furthermore, the inhibition of β-catenin mitigated the accumulation of mesenchymal stroma in A549-hACE2 cells. Additionally, β-catenin knockdown was found to facilitate multi-pathway crosstalk following SARS-CoV-2 infection. The fact that β-catenin overexpression did not exacerbate cellular fibrosis may be attributed to the activation of PPP2R2B.

PMID:40136643 | DOI:10.3390/cells14060394

Radiology. 2025 Mar;314(3):e242292. doi: 10.1148/radiol.242292.

ABSTRACT

Background The clinical, radiologic, and prognostic implications of interstitial pneumonia with autoimmune features (IPAF) in patients with idiopathic interstitial pneumonia and pathologic usual interstitial pneumonia (UIP) have not been fully evaluated. Purpose To compare autoimmune features according to CT patterns for the diagnosis of idiopathic pulmonary fibrosis (IPF) and to assess the diagnostic and prognostic implications of IPAF in patients with IPF-UIP. Materials and Methods This retrospective study included patients with UIP confirmed by surgical lung biopsy between January 2013 and February 2020. Data regarding clinical, radiologic, and pathologic autoimmune features were collected, and patients were diagnosed with IPAF according to current guidelines. CT signs for connective tissue disease (CTD; anterior upper lobe, straightedge, and exuberant honeycombing signs) were also evaluated. Overall survival (OS) was evaluated using Cox proportional hazards models. Results Among 210 patients included (median age, 64 years; IQR, 60-68 years; 158 male patients), 23 (11.0%) had IPAF. Patients with an alternative diagnosis or CT pattern indeterminate for UIP showed a higher prevalence of autoimmune features that were pathologic (38% [33 of 87] vs 20.3% [25 of 123]; P = .005) and serologic (20% [17 of 87] vs 9.8% [12 of 123]; P = .04) and IPAF (4.1% [five of 123] vs 21% [18 of 87]; P < .001) compared with patients with UIP or probable UIP pattern. However, IPAF was not predictive of OS (hazard ratio [HR], 0.81; 95% CI: 0.38, 1.72; P = .58). Lymphoid follicles (HR, 0.59; 95% CI: 0.37, 0.93; P = .02), CT signs for CTD (HR, 0.31; 95% CI: 0.09, 0.99; P = .047), and use of an antifibrotic agent (HR, 0.31; 95% CI: 0.19, 0.51; P < .001) were independently associated with higher OS, and greater extent of fibrosis on CT scans was associated with worse OS (HR, 1.08; 95% CI: 1.05, 1.11; P < .001). Conclusion In patients with IPF-pathologic UIP, serologic and pathologic autoimmune features were associated with indeterminate or alternative CT patterns. Certain histopathologic and radiologic autoimmune features, but not current IPAF criteria, were associated with survival. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Ackman in this issue.

PMID:40131107 | DOI:10.1148/radiol.242292