Respiratory Research最新文献

{"title":"Impact of HHIP gene polymorphisms on phenotypes, serum IL-17 and IL-18 in COPD patients of the Chinese Han population.","authors":"Jiajun Zhang, Di Zhao, Lili Zhang, Xueyan Feng, Beibei Li, Hui Dong, Yanchao Qi, Zun Jia, Fuyun Liu, Shaohui Zhao, Jin Zhang","doi":"10.1186/s12931-024-03020-9","DOIUrl":"10.1186/s12931-024-03020-9","url":null,"abstract":"<p><strong>Background: </strong>Genetic factors, including the Hedgehog Interacting Protein (HHIP) gene, play a crucial role in Chronic Obstructive Pulmonary Disease (COPD) susceptibility. This study examines the association between HHIP gene polymorphisms and COPD susceptibility, phenotypes, and serum IL-17 and IL-18 levels in a Han Chinese population.</p><p><strong>Methods: </strong>A case-control study was conducted with 300 COPD patients and 300 healthy controls in Chinese Han population. Participants underwent genotyping for HHIP gene polymorphisms, pulmonary function tests, and quantitative CT scans. DNA samples were sequenced using a custom chip targeting the HHIP gene. Serum IL-17 and IL-18 levels were measured by enzyme-linked immunosorbent assay. Associations between SNPs, COPD susceptibility, and phenotypes were analyzed using logistic and multiple linear regression models, adjusting for confounders.</p><p><strong>Results: </strong>Our study identified the rs11100865 polymorphism in the HHIP gene as significantly associated with COPD susceptibility (OR 2.479, 95% CI 1.527-4.024, P = 2.39E-04) after screening 114 SNPs through rigorous quality control. Stratified analyses further indicated this association was particularly in individuals aged 60 or older. Serum levels of IL-17 and IL-18 were significantly elevated in COPD patients compared to controls, with rs11100865 showing a notable association with IL-18 levels (B = 49.654, SE = 19.627, P = 0.012). However, no significant associations were observed between rs11100865 and serum IL-17 levels, COPD-related imaging parameters, or clinical phenotypes.</p><p><strong>Conclusion: </strong>This study identified a significant association between HHIP gene polymorphisms and COPD susceptibility in a Han Chinese population, with connections to inflammation, but found no significant associations between this SNP and COPD-related imaging or clinical phenotypes.</p><p><strong>Trial registration: </strong>www.chictr.org.cn ID: ChiCTR2300071579 2023-05-18.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSK3179106 ameliorates lipopolysaccharide-induced inflammation and acute lung injury by targeting P38 MAPK.","authors":"Bin Zheng, Mengying Li, Enhong Lan, Wenting Ding, Lijiao Gao, Yue Tang, Xinyi Wu, Bing Zhang, Yali Zhang, Xiaona Zhu, Hui Zhang","doi":"10.1186/s12931-024-03012-9","DOIUrl":"10.1186/s12931-024-03012-9","url":null,"abstract":"<p><p>Acute lung injury (ALI) is a serious acute respiratory disease that can cause alveolar-capillary barrier disruption and pulmonary edema, respiratory failure and multiple organ dysfunction syndrome. However, there is no effective drugs in clinic until now. GSK3179106 has been reported can alleviate intestinal stress syndrome, but the protective effect of GSK3179106 on ALI has not been elucidated. The present study will evaluate the pharmacological activity of GSK3179106 on lipopolysaccharide (LPS)-induced inflammation and lung injury and clarify its underlying mechanism. We found that GSK3179106 significantly attenuated LPS-induced lung injury in vivo, accompanied by inhibited infiltration of inflammatory cells and reduced expression of inflammatory cytokines. Meanwhile, GSK3179106 dose-dependently reduced the LPS-induced IL-6 expression both in protein and gene levels in macrophages. Mechanistically, GSK3179106 could inhibited the phosphorylation of P38 MAPK induced by LPS. Importantly, results showed that there is a direct combination between GSK3179106 and P38 MAPK. Together, our findings not only clarified the anti-inflammatory activity of GSK3179106 but also discovered its new clinical indications. Therefore, compound GSK3179106 may be a potential candidate for the treatment of acute inflammatory diseases.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-drug resistant Pseudomonas aeruginosa isolation is an independent risk factor for recurrent hemoptysis after bronchial artery embolization in patients with idiopathic bronchiectasis: a retrospective cohort study.","authors":"Jibo Sun, Xiang Tong, Dongguang Wang, Lian Wang, Shijie Zhang, Sitong Liu, Xiu Li, Qingqing Jia, Jiehao Chen, Yao Ma, Hong Fan","doi":"10.1186/s12931-024-03019-2","DOIUrl":"10.1186/s12931-024-03019-2","url":null,"abstract":"<p><strong>Background: </strong>Currently, there is a lack of research on multi-drug resistant Pseudomonas aeruginosa (MDR-PA) isolation in bronchiectasis-related hemoptysis. The aim of this study to analyze the risk factors for recurrent hemoptysis following bronchial artery embolization (BAE) and compare the recurrent hemoptysis-free rates between MDR-PA, non-MDR-PA, and non-PA isolation.</p><p><strong>Methods: </strong>A retrospective study was performed of patients diagnosed with idiopathic bronchiectasis-related recurrent hemoptysis who underwent BAE at an university-affiliated hospital. Patients were categorized based on PA susceptibility tests into non-PA, non-MDR-PA, and MDR-PA groups. Univariate and multivariate Cox regression were conducted to identify independent risk factors for recurrent hemoptysis. The Kaplan-Meier curves was conducted to compare recurrent hemoptysis-free rates after BAE for non-PA, non-MDR-PA, and MDR-PA.</p><p><strong>Results: </strong>A total of 432 patients were included. 181 (41.90%) patients experienced recurrent hemoptysis during a median follow-up period of 25 months. MDR-PA isolation (adjusted hazard ratio (aHR) 2.120; 95% confidence interval (CI) [1.249, 3.597], p = 0.005) was identified as an independent risk factor for recurrent hemoptysis. Antibiotic treatment (aHR 0.666; 95% CI [0.476, 0.932], p = 0.018) reduced the risk of recurrent hemoptysis. The cumulative recurrent hemoptysis-free rates for non-PA, non-MDR-PA, and MDR-PA were as follows: at 3 months, 88.96%, 88.24%, and 75.86%, respectively; at 1 year, 73.13%, 69.10%, and 51.72%; and at 3 years, 61.91%, 51.69%, and 41.10% (p = 0.034).</p><p><strong>Conclusion: </strong>MDR-PA isolation was an independent risk factor of recurrent hemoptysis post-BAE. Reducing the occurrence of MDR-PA may effectively decrease the recurrence rates of hemoptysis.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reinitiating lung development: a novel approach in the management of bronchopulmonary dysplasia.","authors":"Xuewei Cui, Jianhua Fu","doi":"10.1186/s12931-024-02996-8","DOIUrl":"10.1186/s12931-024-02996-8","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is the predominant chronic lung disease in preterm infants, linked with various adverse long-term outcomes. Multiple prenatal and postnatal risk factors can impede lung development, leading to BPD. Current management of BPD relies heavily on pharmacotherapies and alterations in ventilatory strategies. However, these interventions only mitigate BPD symptoms without addressing underlying alveolar, vascular, structural, and functional deficiencies. Given the retarded lung development in infants with BPD and the limitations of existing modalities, new therapeutic approaches are imperative. The induced differentiation of stem/progenitor cells and the spatiotemporal expression patterns of growth factors associated with lung developmental processes are critical for lung development reactivation in BPD, which focuses on stimulating pulmonary vasculogenesis and alveolarization. This review summarizes the process of lung development and offers a comprehensive overview of advancements in therapies designed to reinitiate lung development in BPD. Furthermore, we assessed the potential of these therapies for maintaining lung homeostasis and effectively restoring pulmonary structure and function through stem/progenitor cells and growth factors, which have been widely researched.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clustering-aided prediction of outcomes in patients with idiopathic pulmonary fibrosis.","authors":"Lijun Wang, Peitao Wu, Yi Liu, Divya C Patel, Thomas B Leonard, Hongyu Zhao","doi":"10.1186/s12931-024-03015-6","DOIUrl":"10.1186/s12931-024-03015-6","url":null,"abstract":"<p><strong>Background: </strong>Blood biomarkers predictive of the progression of idiopathic pulmonary fibrosis (IPF) would be of value for research and clinical practice. We used data from the IPF-PRO Registry to investigate whether the addition of \"omics\" data to risk prediction models based on demographic and clinical characteristics improved prediction of the progression of IPF.</p><p><strong>Methods: </strong>The IPF-PRO Registry enrolled patients with IPF at 46 sites across the US. Patients were followed prospectively. Median follow-up was 27.2 months. Prediction models for disease progression included omics data (proteins and microRNAs [miRNAs]), demographic factors and clinical factors, all assessed at enrollment. Data on proteins and miRNAs were included in the models either as raw values or based on clusters in various combinations. Least absolute shrinkage and selection operator (Lasso) Cox regression was applied for time-to-event composite outcomes and logistic regression with L1 penalty was applied for binary outcomes assessed at 1 year. Model performance was assessed using Harrell's C-index (for time-to-event outcomes) or area under the curve (for binary outcomes).</p><p><strong>Results: </strong>Data were analyzed from 231 patients. The models based on demographic and clinical factors, with or without omics data, were the top-performing models for prediction of all the time-to-event outcomes. Relative changes in average C-index after incorporating omics data into models based on demographic and clinical factors ranged from 1.7 to 3.2%. Of the blood biomarkers, surfactant protein-D, serine protease inhibitor A7 and matrix metalloproteinase-9 (MMP-9) were among the top predictors of the outcomes. For the binary outcomes, models based on demographics alone and models based on demographics plus omics data had similar performances. Of the blood biomarkers, CC motif chemokine 11, vascular cell adhesion protein-1, adiponectin, carcinoembryonic antigen and MMP-9 were the most important predictors of the binary outcomes.</p><p><strong>Conclusions: </strong>We identified circulating protein and miRNA biomarkers associated with the progression of IPF. However, the integration of omics data into prediction models that included demographic and clinical factors did not materially improve the performance of the models.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.</p><p><strong>Clinicaltrials: </strong>gov .</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-125b-5p alleviates pulmonary fibrosis by inhibiting TGFβ1-mediated epithelial-mesenchymal transition via targeting BAK1.","authors":"Shuang Zhou, Wenzhao Cheng, Yifei Liu, Hongzhi Gao, Liying Yu, Yiming Zeng","doi":"10.1186/s12931-024-03011-w","DOIUrl":"10.1186/s12931-024-03011-w","url":null,"abstract":"<p><p>This study explores the role and potential mechanisms of microRNA-125b-5p (miR-125b-5p) in pulmonary fibrosis (PF). PF is a typical outcome of many chronic lung diseases, with poor prognosis and the lack of appropriate medical treatment because PF's molecular mechanisms remain poorly understood. In this study, using in vitro and in vivo analyses, we find that miR-125b-5p is likely a potent regulator of lung fibrosis. The findings reveal that, on the one hand, miR-125b-5p not only specifically decreases in the epithelial-mesenchymal transition (EMT) of lung epithelial cells, but also shows a downregulation trend in the lung tissues of mice with PF. On the other hand, overexpression of miR-125b-5p on the cellular and animal levels downregulates EMT and fibrotic phenotypes, respectively. To clarify the molecular mechanism of the \"therapeutic\" effect of miR-125b-5p, we use the target prediction tool combined with a dual luciferase assay and complete a rescue experiment by constructing the overexpression vector of the target gene Bcl-2 homologous antagonist/ killer (BAK1), thus confirming that miR-125b-5p can effectively inhibit EMT and fibrosis process by targeting BAK1 gene. MiR-125b-5p inhibits the EMT in lung epithelial cells by negatively regulating BAK1, while overexpression of miR-125b-5p can alleviate lung fibrosis. The findings suggest that MiR-125b-5p/BAK1 can serve as a potential treatment target for PF.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD.","authors":"Mirco Govoni, Michele Bassi, Luca Girardello, Germano Lucci, François Rony, Rémi Charretier, Dmitry Galkin, Maria Laura Faietti, Barbara Pioselli, Gloria Modafferi, Rui Benfeitas, Martina Bonatti, Daniela Miglietta, Jonathan Clark, Frauke Pedersen, Anne-Marie Kirsten, Kai-Michael Beeh, Oliver Kornmann, Stephanie Korn, Andrea Ludwig-Sengpiel, Henrik Watz","doi":"10.1186/s12931-024-02999-5","DOIUrl":"10.1186/s12931-024-02999-5","url":null,"abstract":"<p><strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition. Given patients with COPD continue to experience exacerbations despite the availability of effective therapies, anti-inflammatory treatments targeting novel pathways are needed. Kinases, notably the phosphoinositide 3-kinases (PI3K), are thought to be involved in chronic airway inflammation, with this pathway proposed as a critical regulator of inflammation and oxidative stress response in COPD. CHF6523 is an inhaled PI3Kδ inhibitor that has shown positive preclinical results. This manuscript reports the results of a study of CHF6523 in patients with stable COPD (chronic bronchitis phenotype), and who had evidence of type-2 inflammation.</p><p><strong>Methods: </strong>This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (N = 44) inhaled CHF6523 in one period, and placebo in the other, both twice daily. The primary objective was to assess the safety and tolerability of CHF6523; the secondary objective was to assess CHF6523 pharmacokinetics. Exploratory endpoints included target engagement (the relative reduction in phosphatidylinositol (3,4,5)-trisphosphate [PIP₃]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics.</p><p><strong>Results: </strong>CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (C_max), reached 15 and 10 min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios < 1.6 for C_max and area under the curve from 0 to 12 h post-dose, and with steady state achieved on Day 20. Target engagement was confirmed by a significant 29.7% reduction from baseline in induced sputum PIP₃ (29.5% reduction vs. placebo; adjusted ratio 0.705 [0.580, 0.856]; p = 0.001), but this did not translate into an anti-inflammatory pharmacodynamic effect, as assessed through measures including biomarkers and multi-omics. Additionally, although CHF6523 was generally well-tolerated, 95.2% of patients reported cough as an adverse event, most mild to moderate and resolving within one-hour post-dose.</p><p><strong>Conclusions: </strong>These data, together with those from other PI3K inhibitors, suggest that PI3Kδ is not a suitable pathway for the management of COPD, as the achieved target engagement did not translate into any pharmacodynamic anti-inflammatory effect.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT04032535); posted 23rd July 2019.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can switching from cigarettes to heated tobacco products reduce consequences of pulmonary infection?","authors":"Tariq A Bhat, Suresh G Kalathil, Noel J Leigh, Maciej L Goniewicz, Yasmin M Thanavala","doi":"10.1186/s12931-024-02992-y","DOIUrl":"10.1186/s12931-024-02992-y","url":null,"abstract":"<p><strong>Rationale: </strong>While tobacco industry data suggests that switching from combustible cigarettes to heated tobacco products (HTPs), like IQOS, may reduce the users' exposure to respiratory toxicants, it is not known if using HTPs impacts the outcomes of acute respiratory infections.</p><p><strong>Objectives: </strong>Does switching from cigarettes to HTPs improve responses to pulmonary infection.</p><p><strong>Methods: </strong>We conducted experiments in which 3 groups of mice were pre-exposed to cigarette smoke for 8 weeks, followed by 8-week exposure to (1) HTPs (tobacco product switching), (2) air (smoking cessation), or (3) continued exposure to cigarette smoke. Pulmonary bacterial clearance and surrogate markers of lung damage were assessed as study outcomes.</p><p><strong>Main results: </strong>Significantly compromised clearance of bacteria from the lungs post-acute challenge occurred in both the switching group and in mice continuously exposed to cigarette smoke. Bacterial clearance, inflammatory T-cell infiltration into the lungs, and albumin leak improved at 12 h post-acute challenge in the switching group compared to mice continuously exposed to cigarette smoke. Bacterial clearance, total lung immune-cell infiltration, inflammatory T-cell infiltration into the lungs, the content of total proteins in the BAL, and albumin leak measured post-acute challenge were compromised in the switching group compared to mice in the cessation group. Switching from cigarettes to HTPs did not improve lung myeloperoxidase and neutrophil elastase levels (markers for lung inflammation and damage), which, however, were significantly reduced in the cessation group.</p><p><strong>Conclusions: </strong>This study reveals only a modest improvement in respiratory infection outcomes after switching exposure from cigarettes to HTPs and significantly compromised outcomes compared to a complete cessation of exposure to all tobacco products.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma genome-wide mendelian randomization identifies potentially causal genes in idiopathic pulmonary fibrosis.","authors":"Kun Zhang, Puyu Shi, Anqi Li, Jiejun Zhou, Mingwei Chen","doi":"10.1186/s12931-024-03008-5","DOIUrl":"https://doi.org/10.1186/s12931-024-03008-5","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic pulmonary fibrosis (IPF) is a complex lung disease with a very poor prognosis. Existing drugs for the treatment of IPF are still insufficient. Therefore, there is still a need to explore new drug targets for preventing and treating IPF.</p><p><strong>Methods: </strong>We included quantitative trait loci (QTL) for genes, DNA methylation, and proteins in plasma, as well as the summary statistics for IPF. Genetic variants located within 500 kb of the gene and strongly associated with plasma exposure were used as instrumental variables. The causal association between plasma exposures and IPF was primarily estimated using summary-data-based Mendelian randomization (SMR) analysis. Five other MR methods and sensitivity analyses were employed to validate the SMR results. Bayesian tests for colocalization between QTL and IPF risk loci further strengthen the MR results.</p><p><strong>Results: </strong>We identified three genes and five DNA methylation sites causally associated with IPF by SMR analysis, validation of MR analysis, sensitivity analysis, and colocalization analysis. BTRC and LINC01252 were negatively associated with IPF risk (OR: 0.30, 95% CI: 0.17-0.54, FDR_SMR = 0.029; OR: 0.85, 95% CI: 0.78-0.92, FDR_SMR = 0.043), and RIPK4 was positively associated with IPF risk (OR: 2.60, 95% CI: 1.64-4.12, FDR_SMR = 0.031). cg00045227 (OR8U8, OR: 1.16, 95% CI: 1.08-1.24, FDR_SMR = 0.010), cg00577578 (GBAP1, OR: 1.23, 95% CI: 1.12-1.36, FDR_SMR = 0.014), cg14222479 (ARPM1, OR: 3.17, 95% CI: 1.98-5.08, FDR_SMR = 0.001), and cg19263494 (PMF1, OR: 1.20, 95% CI: 1.10-1.30, FDR_SMR = 0.012) were positively associated with the risk of IPF, whereas cg07163735 (MAPT, OR: 0.22, 95% CI: 0.11-0.45, FDR_SMR = 0.013) was negatively correlated with the risk of IPF.</p><p><strong>Conclusions: </strong>This study demonstrated that genetically determined plasma levels of the BTRC, RIPK4, and LINC01252 genes, as well as methylation levels of cg00045227 (OR8U8), cg00577578 (GBAP1), cg07163735 (MAPT), cg14222479 (ARPM1), and cg19263494 (PMF1), have causal influences on the risk of IPF.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of inhaled beclometasone dipropionate/formoterol fumarate/glycopyrronium vs. beclometasone dipropionate/formoterol fumarate and placebo on lung hyperinflation and exercise endurance in chronic obstructive pulmonary disease: a randomised controlled trial.","authors":"Henrik Watz, Anne-Marie Kirsten, Andrea Ludwig-Sengpiel, Matthias Krüll, Robert M Mroz, George Georges, Guido Varoli, Rémi Charretier, Mauro Cortellini, Andrea Vele, Dmitry Galkin","doi":"10.1186/s12931-024-02993-x","DOIUrl":"https://doi.org/10.1186/s12931-024-02993-x","url":null,"abstract":"<p><strong>Background: </strong>The single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD.</p><p><strong>Methods: </strong>This double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7-10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3.</p><p><strong>Results: </strong>Of 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate.</p><p><strong>Conclusions: </strong>In patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT05097014), registered 27th October 2021.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}