Eur J Phys Rehabil Med. 2025 Apr 3. doi: 10.23736/S1973-9087.25.08778-7. Online ahead of print.

ABSTRACT

INTRODUCTION: The efficacy of pulmonary rehabilitation (PR) in improving health-related quality of life (HRQoL) in patients with interstitial lung disease (ILD) still have some unresolved issues. This study aimed to identify this gap by using the 36-Item Short Form Survey (SF-36) to assess the advantages and disadvantages of PR in improving the HRQoL of patients with ILD.

EVIDENCE ACQUISITION: Self-controlled before-and-after interventional design research related to PR and ILD published in English were retrieved from PubMed, Embase, Web of Science, Scopus, Ovid, and Cochrane Library from inception to May 19, 2024. Data collected from the included studies were general clinical characteristics, study sample size, SF-36 physical component summary (PCS) score, SF-36 mental component summary (MCS) score, scores of the eight domains (physical function, role physical, bodily pain, general health, vitality, social function, role emotional, and mental health), PR time, and main elements of PR. Subgroup analysis was performed based on the PR time and ILD type. Sensitivity analysis was conducted by excluding one study at a time. Publication bias was assessed using Egger's Test, and the reliability of the studies was determined using the funnel plot and trim-and-fill method. Changes in SF-36 domain scores after PR were presented in a radar chart.

EVIDENCE SYNTHESIS: Pooled analysis of 15 studies involving 1289 patients with ILD who underwent PR showed that the patients had significantly higher PCS scores (weighted mean difference [WMD]=2.07, 95% CI: 1.06, 3.09) and MCS scores (WMD=4.48, 95% CI: 3.21, 5.76) after PR. According to disease types, subgroup analyses showed that patients with idiopathic pulmonary fibrosis had significantly higher PCS scores (WMD=3.15, 95% CI: 0.05, 6.24) but no change in MCS scores after PR (WMD=1.97, 95% CI: -1.91, 5.85). Additionally, subgroup analysis based on PR time revealed that the PCS scores of patients with ILD were significantly increased after <8 weeks of PR (WMD=2.09, 95% CI: 1.02, 3.17) but not after ≥8 weeks of PR (WMD=1.94, 95% CI: -1.05, 4.93, P=0.204). All included studies were of good quality, and the pooled and subgroup results were robust without publication bias.

CONCLUSIONS: In patients with ILD, PR less than 8 weeks effectively improved the physical and mental HRQoL, but not the social function. Future studies should focus on determining the optimal PR time for enhancing HRQoL in patients with ILD and evaluating the efficacy of PR in different ILD types and other HRQoL domains.

PMID:40178411 | DOI:10.23736/S1973-9087.25.08778-7

Respir Res. 2025 Apr 2;26(1):123. doi: 10.1186/s12931-025-03195-9.

ABSTRACT

BACKGROUND: Cardiopulmonary exercise testing (CPET) is feasible, valid, reliable, and clinically useful in interstitial lung disease (ILD). However, maximal CPET values are often presented relative to body mass, whereas fat-free mass (FFM) may better reflect metabolically active muscle during exercise. Moreover, despite the value of maximal parameters, people with ILD do not always exercise maximally and therefore clinically relevant submaximal parameters must be identified. Therefore, this study assessed peak oxygen uptake (VO2peak) relative to FFM, identifying the validity of common scaling techniques; as well as characterising the oxygen uptake efficiency slope (OUES) and plateau (OUEP) as possible submaximal parameters.

METHODS: Participants with ILD underwent assessment of body composition and CPET via cycle ergometry during a single study visit. To determined effectiveness of scaling for body size, both body mass and FFM were scaled using ratio-standard (X/Y) and allometric (X/Yb) techniques. Pearsons's correlations determined agreement between OUES, OUEP, and parameters of lung function. Cohens kappa (κ) assessed agreement between OUES, OUEP and VO2peak.

RESULTS: A total of 24 participants (7 female; 69.8 ± 7.5 years; 17 with idiopathic pulmonary fibrosis) with ILD completed the study. Maximal exercise parameters did not require allometric scaling, and when scaled to FFM, it was shown that women have a significantly higher VO2peak than men (p = 0.044). Results also indicated that OUEP was significantly and positively correlated with DLCO (r = 0.719, p < 0.001), and held moderate agreement with VO2peak (κ = 0.50, p < 0.01).

CONCLUSION: This study identified that ratio-standard scaling is sufficient in removing residual effects of body size from VO2peak, and that VO2peak is higher in women when FFM is considered. Encouragingly, this study also identified OUEP as a possible alternative submaximal marker in people with ILD, and thus warrants further examination.

PMID:40176026 | DOI:10.1186/s12931-025-03195-9

Respir Investig. 2025 Apr 1;63(3):431-437. doi: 10.1016/j.resinv.2025.03.016. Online ahead of print.

ABSTRACT

BACKGROUND: The effect of combining high fraction of inspired oxygen (FIO2) and high flow through a high-flow nasal cannula (HFNC) on exercise tolerance in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) remains unclear.

METHODS: This prospective, single-blind, randomized, crossover study included patients with COPD (n = 25) and IPF (n = 25). The patients performed a 6-min walking test (6 MWT) while attached to a battery-supplied portable HFNC device under the following four conditions: FIO2 set to a minimum percutaneous oxygen saturation (SpO2) of 86-88 % during 6 MWT with a flow rate of 10 L/min (LOLF) or 50 L/min (LOHF); and FIO2 set to a minimum SpO2 of 92-94 % with a flow rate of 10 L/min (HOLF) or 50 L/min (HOHF).

RESULTS: In both groups, the 6-min walking distance (6 MWD) was significantly greater for HOHF than for LOLF (COPD: 323.2 ± 77.6 m vs. 268.6 ± 87.3 m, respectively, p < 0.0001 and IPF: 406 ± 50.7 m vs. 372.3 ± 50.9 m, respectively, p < 0.0001). In the analysis of the interaction effects for the 6 MWD, the combination of high FIO2 and high flow resulted in an additional 15.9-m extension of the 6 MWD (95 % confidence interval: 0.34-31.5; p = 0.050). The interaction between IPF and high-flow was -14.0 m, suggesting a less pronounced extension effect compared with COPD (95 % confidence interval: -29.5-1.6; p = 0.085).

CONCLUSION: The combination of high FIO2 and high flow through an HFNC may improve exercise tolerance in patients with COPD and IPF.

PMID:40174242 | DOI:10.1016/j.resinv.2025.03.016

Eur Rev Med Pharmacol Sci. 2025 Mar;29(3):123-134. doi: 10.26355/eurrev_202503_37125.

ABSTRACT

The interstitial lung disease (ILD) field is rapidly expanding as new insights highlight novel mechanisms and procedures that influence epidemiology, diagnosis, and treatment. The aim of this review is to report on recent advancements and future perspectives in clinical management and research in ILD, particularly in idiopathic pulmonary fibrosis (IPF), for the most common ILD. Whilst high-resolution computed tomography (HRCT) remains the gold standard for diagnosis, we focus on newer diagnostic techniques, including IPF genome analysis and epigenetics, biomarkers, bronchoscope robotic navigation, and transbronchial lung cryo biopsy for improving diagnostic accuracy. Further, we report IPF associated with pulmonary hypertension Group 3 and scores for defining disease progression. Positron emission tomography/computed tomography, treatment with prostacyclin and antifibrotic drugs, and lung transplantation as potential treatments for end-stage IPF are discussed. Lastly, we discuss contemporary perspectives on interstitial lung abnormalities (ILA), IPF associated with lung cancer, and the use of artificial intelligence (AI) for ILD diagnosis and monitoring.

GRAPHICAL ABSTRACT: https://www.europeanreview.org/wp/wp-content/uploads/123-134.jpg.

PMID:40171787 | DOI:10.26355/eurrev_202503_37125

Hereditas. 2025 Apr 1;162(1):50. doi: 10.1186/s41065-025-00401-y.

ABSTRACT

PURPOSE: Ubiquitination plays a crucial role in various diseases. This study aims to explore the potential ubiquitination related genes in IPF.

METHODS: The gene microarray dataset GSE24206 was obtained from GEO database. Subsequently, through differential expression analysis and molecular signatures database, we obtained 1734 differentially expressed genes and 742 ubiquitination related genes. Through the venn diagram analysis, we obtained 53 differentially expressed ubiquitination related genes. Then, gene-ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, protein-protein interactions (PPI) and gene set enrichment analysis (GSEA) were applied for the differentially expressed ubiquitination related genes. Finally, the expression of CDC20 and ITCH in IPF patients and cells were validated by qPCR and western blot assay.

RESULTS: A total of 53 differentially expressed ubiquitination related genes (36 up-regulated genes and 17 down-regulated genes) were identified between 17 IPF patients and 6 healthy controls. GO and KEGG enrichment analysis of ubiquitination related genes mainly involved in regulation of protein ubiquitination, regulation of post-translational protein modification and ubiquitin mediated proteolysis. The PPI results demonstrated that these ubiquitination related genes interacted with each other. The GSEA analysis results for some of the hub genes mainly involved epithelial mesenchymal transition, inflammatory response, hypoxia, and apoptosis. The experiment expression level of CDC20 and ITCH in IPF patients and IPF cells were consistent with the bioinformatics analysis results.

CONCLUSION: We identified 53 potential ubiquitination related genes of IPF through bioinformatics analysis. CDC20 and ITCH and other ubiquitination related genes may influence the development of IPF through epithelial mesenchymal transition and inflammatory response. Our research findings provide insights into the mechanisms of fibrosis and may provide evidence for potential therapeutic targets for fibrosis.

PMID:40170095 | DOI:10.1186/s41065-025-00401-y

J Clin Lab Anal. 2025 Apr 1:e70026. doi: 10.1002/jcla.70026. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease with a complex pathogenesis involving multiple immune cells. This study investigates the relationship between immune cells and IPF using Mendelian randomization (MR) analysis.

METHODS: A two-sample MR analysis was performed using genome-wide association studies (GWAS) and immune cell databases by R software. We analyzed data from 1028 European individuals with IPF, focusing on 731 immune traits. The primary method of analysis was inverse variance weighting (IVW), supplemented with sensitivity analyses, including MR-Egger regression and MR-PRESSO, to detect and correct for pleiotropy.

RESULTS: The MR analysis identified six immune panels and 23 immune traits significantly associated with IPF, including five traits that increase and 18 traits that decrease IPF risk. Notable traits increasing IPF risk included switched memory B-cells (OR = 1.27, p = 0.0029) and IgD- CD38dim B-cells (OR = 1.08, p = 0.0449). Traits associated with a reduced IPF risk included central memory CD4+ T-cells (%CD4+, OR = 0.96, p = 0.0489), CD20 on naive-mature B-cells (OR = 0.94, p = 0.0499), and CD33br HLA-DR+ absolute count (AC) (OR = 0.93, p = 0.0489). There was no significant causal relationship between IPF disease and some immune traits (p > 0.05).

CONCLUSION: This study suggests a potential causal link between specific immune cell traits and the development of IPF, providing new insights into the disease's immunological mechanisms. Future research should focus on validating these findings in larger, more diverse populations to inform drug development and therapeutic strategies.

PMID:40167279 | DOI:10.1002/jcla.70026

3 Biotech. 2025 Apr;15(4):102. doi: 10.1007/s13205-025-04272-y. Epub 2025 Mar 29.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lung disease with an unknown etiology and a short survival rate. There is no accurate method of early diagnosis, and it involves computed tomography (CT) or lung biopsy. Since diagnostic methods are not accurate due to their similarity to other lung pathologies, discovering new biomarkers is a key issue for diagnosticians. Currently, the use of ccf-DNA (circulating cell-free deoxyribonucleic acid) is an important focus due to its association with IPF-induced alterations in metabolic pathways, such as amino acid metabolism, energy metabolism, and lipid metabolism pathways. Other biomarkers associated with metabolic changes have been found, and they are related to changes in type II/type I alveolar epithelial cells (AECs I/II), changes in extracellular matrix (ECM), and inflammatory processes. Currently, IPF pathogenetic treatment remains unknown, and the mortality rates are increasing, and the patients are diagnosed at a late stage. Signaling pathways and metabolic dysfunction have a significant role in the disease occurrence, particularly the transforming growth factor-β (TGF-β) signaling pathway, which plays an essential role. TGF-β, Wnt, Hedgehog (Hh), and integrin signaling are the main drivers of fibrosis. These pathways activate the transformation of fibroblasts into myofibroblasts, extracellular matrix (ECM) deposition, and tissue remodeling fibrosis. Therapy targeting diverse signaling pathways to slow disease progression is crucial in the treatment of IPF. Two antifibrotic medications, including pirfenidone and nintedanib, are Food and Drug Administration (FDA)-approved for treatment. ccf-DNA could become a new biomarker for IPF diagnosis to detect the disease at the early stage, while FDA-approved therapies could help to prevent late conditions from forming and decrease mortality rates.

PMID:40165930 | PMC:PMC11954786 | DOI:10.1007/s13205-025-04272-y

Clin Respir J. 2025 Apr;19(4):e70072. doi: 10.1111/crj.70072.

ABSTRACT

BACKGROUND: This study aims to summarize the similarities and differences in immune cell characteristics, and potential therapeutic targets between systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF).

METHODS: This study included SSc-ILD and SSc-nonILD patients who were admitted to Beijing Chaoyang Hospital between April 4th, 2013, to June 30th, 2023. Publicly available datasets, including peripheral blood monocular cell (pbmc) single-cell data, SSc, SSc-ILD pbmc transcriptome data, and SSc-ILD, IPF lung tissue transcriptome data were analyzed. Statistical analyses were conducted using the SPSS and R software, employing standard statistical methods and bioinformatics packages such as Seurat, DESeq2, enrichR, and CellChat.

RESULTS: The results revealed that the CD4+/CD8+ T cell ratio of pbmc in SSc-ILD patients was significantly higher than in SSc-nonILD patients. In IPF patients, an elevated CD4+/CD8+ T cell ratio was also observed in progressive group, and Treg and mature CD4+ T cells might cause this change. JAK-STAT pathway and the cytokine-cytokine receptor interaction pathway were activated in peripheral blood T cells of IPF patients. The CD30, CD40, and FLT3 signaling pathways were found to play crucial roles in T cell interactions with other immune cells among IPF patients. SPA17 as a commonly upregulated gene among SSc, SSc-ILD, and IPF pbmc and lung, with its expression correlating positively with disease severity and lung function progression.

CONCLUSION: CD4+/CD8+ T cell ratio might associate with ILD initiation and progression; Treg cells and mature CD4+ T cells play key roles of it. SPA17 might serve as a pan-ILD marker and associated with lung function progression.

PMID:40165483 | DOI:10.1111/crj.70072

J Gene Med. 2025 Apr;27(4):e70018. doi: 10.1002/jgm.70018.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an unknown etiology and complex pathophysiology that are not fully understood. The disease involves intricate cellular interplay, particularly among various immune cells. Currently, there is no treatment capable of reversing the fibrotic process or aiding lung regeneration. Hepatocyte growth factor (HGF) has demonstrated antifibrotic properties, whereas the adoptive transfer of modified T cells is a well-established treatment for various malignancies. We aimed to understand the dynamics of T cells in the progression of lung fibrosis and to study the therapeutic benefit of adoptive T cell transfer in a bleomycin-injured mouse lung (BLM) model.

METHODS: T cells were isolated from the spleen of naïve mice and transfected in vitro with mouse HGF plasmid and were administered intratracheally to the mice lungs 7 days post-bleomycin injury to the lung. Lung tissue and bronchoalveolar lavage were collected and analyzed using flow cytometry, histology, qRT-PCR, ELISA, and hydroxyproline assay.

RESULTS: Our findings demonstrate the successful T cell therapy of bleomycin-induced lung injury through the adoptive transfer of HGF-transfected T cells in mice. This treatment resulted in decreased collagen deposition and a balancing of immune cell exhaustion and cytokine homeostasis compared with untreated controls. In vitro testing showed enhanced apoptosis in myofibroblasts induced by HGF-overexpressing T cells.

CONCLUSIONS: Taken together, our data highlight the great potential of adoptive T cell transfer as an emerging therapy to counteract lung fibrosis.

PMID:40159455 | DOI:10.1002/jgm.70018

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