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Impact of HHIP gene polymorphisms on phenotypes, serum IL-17 and IL-18 in COPD patients of the Chinese Han population. HHIP基因多态性对中国汉族慢性阻塞性肺病患者表型、血清IL-17和IL-18的影响
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-28 DOI: 10.1186/s12931-024-03020-9
Jiajun Zhang, Di Zhao, Lili Zhang, Xueyan Feng, Beibei Li, Hui Dong, Yanchao Qi, Zun Jia, Fuyun Liu, Shaohui Zhao, Jin Zhang

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: www.chictr.org.cn ID: ChiCTR2300071579 2023-05-18.

背景:包括刺猬互作蛋白(HHIP)基因在内的遗传因素在慢性阻塞性肺病(COPD)易感性中起着至关重要的作用。本研究探讨了汉族人群中 HHIP 基因多态性与 COPD 易感性、表型以及血清 IL-17 和 IL-18 水平之间的关系:方法:对中国汉族人群中的 300 名慢性阻塞性肺病患者和 300 名健康对照者进行了病例对照研究。参与者接受了 HHIP 基因多态性基因分型、肺功能测试和定量 CT 扫描。使用针对 HHIP 基因的定制芯片对 DNA 样本进行测序。血清IL-17和IL-18水平通过酶联免疫吸附试验测定。使用逻辑和多元线性回归模型分析了SNPs、慢性阻塞性肺病易感性和表型之间的关联,并对混杂因素进行了调整:结果:通过严格的质量控制筛选出 114 个 SNPs 后,我们的研究发现 HHIP 基因中的 rs11100865 多态性与 COPD 易感性显著相关(OR 2.479,95% CI 1.527-4.024,P = 2.39E-04)。分层分析进一步表明,这种关联在 60 岁或以上的人群中尤为明显。与对照组相比,慢性阻塞性肺病患者血清中的IL-17和IL-18水平明显升高,其中rs11100865与IL-18水平有显著关联(B = 49.654,SE = 19.627,P = 0.012)。然而,在rs11100865与血清IL-17水平、COPD相关影像学参数或临床表型之间没有观察到明显的关联:本研究发现,在汉族人群中,HHIP 基因多态性与慢性阻塞性肺病易感性之间存在显著关联,且与炎症有关,但未发现该 SNP 与慢性阻塞性肺病相关影像学或临床表型之间存在显著关联。试验注册:www.chictr.org.cn ID:ChiCTR2300071579 2023-05-18.
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引用次数: 0
GSK3179106 ameliorates lipopolysaccharide-induced inflammation and acute lung injury by targeting P38 MAPK. GSK3179106 通过靶向 P38 MAPK 改善脂多糖诱导的炎症和急性肺损伤。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-28 DOI: 10.1186/s12931-024-03012-9
Bin Zheng, Mengying Li, Enhong Lan, Wenting Ding, Lijiao Gao, Yue Tang, Xinyi Wu, Bing Zhang, Yali Zhang, Xiaona Zhu, Hui Zhang

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.

急性肺损伤(ALI)是一种严重的急性呼吸道疾病,可导致肺泡-毛细血管屏障破坏和肺水肿、呼吸衰竭及多器官功能障碍综合征。然而,到目前为止,临床上还没有有效的药物。有报道称GSK3179106能缓解肠应激综合征,但GSK3179106对ALI的保护作用尚未阐明。本研究将评估 GSK3179106 对脂多糖(LPS)诱导的炎症和肺损伤的药理活性,并阐明其潜在机制。我们发现,GSK3179106能显著减轻LPS诱导的体内肺损伤,同时抑制炎症细胞的浸润,降低炎症细胞因子的表达。同时,GSK3179106剂量依赖性地降低了LPS诱导的IL-6在巨噬细胞中的蛋白和基因表达。从机理上讲,GSK3179106 可抑制 LPS 诱导的 P38 MAPK 磷酸化。重要的是,研究结果表明 GSK3179106 与 P38 MAPK 之间存在直接的结合。综上所述,我们的研究结果不仅阐明了 GSK3179106 的抗炎活性,还发现了其新的临床适应症。因此,化合物 GSK3179106 可能是治疗急性炎症性疾病的潜在候选药物。
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引用次数: 0
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. 特发性支气管扩张症患者支气管动脉栓塞术后复发咯血的独立风险因素:一项回顾性队列研究。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-26 DOI: 10.1186/s12931-024-03019-2
Jibo Sun, Xiang Tong, Dongguang Wang, Lian Wang, Shijie Zhang, Sitong Liu, Xiu Li, Qingqing Jia, Jiehao Chen, Yao Ma, Hong Fan

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

背景:目前,缺乏对支气管扩张相关咯血中多重耐药铜绿假单胞菌(MDR-PA)分离的研究。本研究旨在分析支气管动脉栓塞术(BAE)后复发性咯血的风险因素,并比较MDR-PA、非MDR-PA和非PA分离术的无复发性咯血率:一项回顾性研究针对在大学附属医院接受 BAE 的特发性支气管扩张相关复发性咯血患者。根据 PA 药敏试验将患者分为非 PA 组、非 MDR-PA 组和 MDR-PA 组。通过单变量和多变量考克斯回归来确定复发性咯血的独立风险因素。采用 Kaplan-Meier 曲线比较非 PA、非 MDR-PA 和 MDR-PA 患者 BAE 后的无复发性咯血率:结果:共纳入 432 例患者。181例(41.90%)患者在中位 25 个月的随访期间出现复发性咯血。MDR-PA 分离(调整后危险比 (aHR) 2.120; 95% 置信区间 (CI) [1.249, 3.597], p = 0.005)被确定为复发性咯血的独立危险因素。抗生素治疗(aHR 0.666;95% CI [0.476,0.932],p = 0.018)降低了复发性咯血的风险。非 MDR-PA、非 MDR-PA 和 MDR-PA 的累计无复发性咯血率如下:3 个月时,分别为 88.96%、88.24% 和 75.86%;1 年时,分别为 73.13%、69.10% 和 51.72%;3 年时,分别为 61.91%、51.69% 和 41.10%(P = 0.034):结论:MDR-PA 分离是急性呼吸衰竭后复发性咯血的独立风险因素。减少 MDR-PA 的发生可有效降低咯血的复发率。
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引用次数: 0
Reinitiating lung development: a novel approach in the management of bronchopulmonary dysplasia. 重启肺部发育:治疗支气管肺发育不良的新方法。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-24 DOI: 10.1186/s12931-024-02996-8
Xuewei Cui, Jianhua Fu

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.

支气管肺发育不良(BPD)是早产儿最主要的慢性肺部疾病,与各种不良的长期预后有关。多种产前和产后风险因素会阻碍肺部发育,从而导致 BPD。目前对 BPD 的治疗主要依赖于药物疗法和通气策略的改变。然而,这些干预措施只能缓解 BPD 的症状,却无法解决潜在的肺泡、血管、结构和功能缺陷。鉴于BPD婴儿肺部发育迟缓以及现有模式的局限性,新的治疗方法势在必行。干细胞/祖细胞的诱导分化以及与肺部发育过程相关的生长因子的时空表达模式对 BPD 的肺部发育再激活至关重要,其重点在于刺激肺血管生成和肺泡化。本综述总结了肺发育过程,并全面概述了旨在重启 BPD 肺发育的疗法的进展。此外,我们还评估了这些疗法通过干细胞/祖细胞和生长因子维持肺稳态并有效恢复肺结构和功能的潜力。
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引用次数: 0
Clustering-aided prediction of outcomes in patients with idiopathic pulmonary fibrosis. 特发性肺纤维化患者预后的聚类辅助预测。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-23 DOI: 10.1186/s12931-024-03015-6
Lijun Wang, Peitao Wu, Yi Liu, Divya C Patel, Thomas B Leonard, Hongyu Zhao

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.

Clinicaltrials: gov .

背景:预测特发性肺纤维化(IPF)进展的血液生物标志物将对研究和临床实践具有重要价值。我们利用 IPF-PRO 登记处的数据,研究在基于人口统计学和临床特征的风险预测模型中添加 "omics "数据是否能改善对 IPF 进展的预测:IPF-PRO登记处在全美46个地点登记了IPF患者。对患者进行了前瞻性随访。中位随访时间为 27.2 个月。疾病进展预测模型包括omics数据(蛋白质和microRNAs [miRNAs])、人口统计学因素和临床因素,所有这些都在入组时进行了评估。蛋白质和 miRNAs 数据以原始值或基于不同组合的聚类被纳入模型。时间到事件复合结果采用最小绝对收缩和选择算子(Lasso)Cox回归,1年评估的二元结果采用带L1惩罚的Logistic回归。使用哈雷尔 C 指数(针对时间到事件的结果)或曲线下面积(针对二元结果)评估模型性能:结果:分析了 231 名患者的数据。基于人口统计学和临床因素的模型,无论是否包含 omics 数据,都是预测所有时间到事件结果的最佳模型。在基于人口统计学和临床因素的模型中加入全息数据后,平均 C 指数的相对变化范围为 1.7% 至 3.2%。在血液生物标志物中,表面活性蛋白-D、丝氨酸蛋白酶抑制剂 A7 和基质金属蛋白酶-9(MMP-9)是预测结果的首要指标。对于二元结果,仅基于人口统计学数据的模型和基于人口统计学数据加 Omics 数据的模型表现相似。在血液生物标志物中,CC motif趋化因子11、血管细胞粘附蛋白-1、脂肪连素、癌胚抗原和MMP-9是预测二元结局的最重要指标:我们发现了与 IPF 进展相关的循环蛋白和 miRNA 生物标志物。结论:我们发现了与 IPF 进展相关的循环蛋白和 miRNA 生物标志物,但将 omics 数据整合到包含人口统计学和临床因素的预测模型中并不能显著提高模型的性能:试验注册:ClinicalTrials.gov;编号:NCT01915511;注册日期:2013 年 8 月 5 日;URL:www.Clinicaltrials: gov .
{"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}
引用次数: 0
MiR-125b-5p alleviates pulmonary fibrosis by inhibiting TGFβ1-mediated epithelial-mesenchymal transition via targeting BAK1. MiR-125b-5p 通过靶向 BAK1 抑制 TGFβ1 介导的上皮-间充质转化,从而减轻肺纤维化。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-19 DOI: 10.1186/s12931-024-03011-w
Shuang Zhou, Wenzhao Cheng, Yifei Liu, Hongzhi Gao, Liying Yu, Yiming Zeng

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.

本研究探讨了microRNA-125b-5p(miR-125b-5p)在肺纤维化(PF)中的作用和潜在机制。肺纤维化是许多慢性肺部疾病的典型结果,预后较差,且由于肺纤维化的分子机制尚不清楚,因此缺乏适当的医疗手段。本研究通过体外和体内分析发现,miR-125b-5p 可能是肺纤维化的一个有效调节因子。研究结果表明,一方面,miR-125b-5p 不仅在肺上皮细胞的上皮-间质转化(EMT)过程中特异性下降,而且在肺纤维化小鼠的肺组织中也呈下调趋势。另一方面,在细胞和动物水平上过表达 miR-125b-5p 可分别下调 EMT 和纤维化表型。为了阐明miR-125b-5p "治疗 "作用的分子机制,我们利用靶点预测工具结合双荧光素酶检测,并通过构建靶基因Bcl-2同源拮抗剂/杀伤剂(BAK1)的过表达载体完成了拯救实验,从而证实了miR-125b-5p能通过靶向BAK1基因有效抑制EMT和纤维化过程。MiR-125b-5p通过负调控BAK1抑制肺上皮细胞的EMT,而过表达miR-125b-5p可缓解肺纤维化。研究结果表明,MiR-125b-5p/BAK1可作为肺纤维化的潜在治疗靶点。
{"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}
引用次数: 0
CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD. CHF6523 的数据表明,磷酸肌酸 3- 激酶 delta 同工酶不是治疗慢性阻塞性肺病的合适靶点。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-19 DOI: 10.1186/s12931-024-02999-5
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

Background: 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.

Methods: 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.

Results: CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (Cmax), 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 Cmax 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov (NCT04032535); posted 23rd July 2019.

背景:慢性阻塞性肺病(COPD)是一种慢性炎症。尽管有有效的治疗方法,但慢性阻塞性肺病患者的病情仍在不断加重,因此需要针对新通路的抗炎治疗。激酶,尤其是磷酸肌酸 3- 激酶 (PI3K),被认为参与了慢性气道炎症,这一途径被认为是慢性阻塞性肺病中炎症和氧化应激反应的关键调节因子。CHF6523 是一种吸入式 PI3Kδ 抑制剂,临床前研究已取得积极成果。本手稿报告了一项针对慢性阻塞性肺病(慢性支气管炎表型)稳定期患者的 CHF6523 研究结果,这些患者有证据表明存在 2 型炎症:这项随机、双盲、安慰剂对照、双向交叉研究包括两个为期 28 天的治疗期,中间有 28 天的冲洗期。患者(44 人)在一个疗程中吸入 CHF6523,在另一个疗程中吸入安慰剂,每天两次。主要目的是评估CHF6523的安全性和耐受性;次要目的是评估CHF6523的药代动力学。探索性终点包括目标参与度(磷脂酰肌醇(3,4,5)-三磷酸[PIP3]的相对减少量)、药效学评估(如气流阻塞和过度充气),并利用蛋白质组学和转录组学确定药物反应的生物标志物:CHF6523的血浆药代动力学特征是早期最大浓度(Cmax),分别在用药后第1天和第28天的15分钟和10分钟达到,随后迅速下降。第 28 天的全身暴露显示出有限的蓄积,最大比值和曲线下面积从给药后 0 到 12 小时不等,第 20 天达到稳态。诱导痰 PIP3 比基线显著降低 29.7%(与安慰剂相比降低 29.5%;调整比值比为 0.705 [0.580, 0.856];p = 0.001),证实了目标参与,但这并没有转化为抗炎药效学效应,评估指标包括生物标志物和多组学。此外,尽管CHF6523的耐受性普遍良好,但95.2%的患者报告了咳嗽这一不良反应,其中大多数为轻度至中度,并在服药后一小时内缓解:这些数据以及其他 PI3K 抑制剂的数据表明,PI3Kδ 并非治疗慢性阻塞性肺病的合适途径,因为实现的目标参与并未转化为任何药效学抗炎作用:试验注册:ClinicalTrials.gov (NCT04032535);2019年7月23日发布。
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引用次数: 0
Can switching from cigarettes to heated tobacco products reduce consequences of pulmonary infection? 从香烟改用加热烟草制品能否减少肺部感染的后果?
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-19 DOI: 10.1186/s12931-024-02992-y
Tariq A Bhat, Suresh G Kalathil, Noel J Leigh, Maciej L Goniewicz, Yasmin M Thanavala

Rationale: 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.

Objectives: Does switching from cigarettes to HTPs improve responses to pulmonary infection.

Methods: 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.

Main results: 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.

Conclusions: 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.

理由:虽然烟草行业的数据表明,从可燃卷烟转向加热烟草制品(HTPs),如IQOS,可能会减少使用者暴露于呼吸道毒物的机会,但使用加热烟草制品是否会影响急性呼吸道感染的结果尚不清楚:从香烟转向 HTPs 是否会改善对肺部感染的反应:我们进行了这样的实验:3 组小鼠先暴露于香烟烟雾 8 周,然后暴露于(1)HTPs(更换烟草制品)、(2)空气(戒烟)或(3)继续暴露于香烟烟雾 8 周。肺部细菌清除率和肺损伤替代标志物作为研究结果进行评估:主要结果:在转换组和持续暴露于香烟烟雾的小鼠中,急性挑战后肺部细菌清除率明显下降。与持续暴露于香烟烟雾中的小鼠相比,切换组在急性挑战后 12 小时的细菌清除率、肺部炎性 T 细胞浸润和白蛋白泄漏情况均有所改善。与戒烟组小鼠相比,转烟组小鼠在急性挑战后测量的细菌清除率、肺部免疫细胞总浸润、肺部炎症T细胞浸润、BAL中总蛋白含量和白蛋白渗漏均受到影响。从吸食香烟转为吸食 HTPs 并未改善肺髓过氧化物酶和中性粒细胞弹性蛋白酶水平(肺部炎症和损伤的标志物),但戒烟组的肺髓过氧化物酶和中性粒细胞弹性蛋白酶水平显著降低:这项研究表明,从接触香烟转为接触 HTPs 后,呼吸道感染的治疗效果仅略有改善,而与完全停止接触所有烟草制品相比,治疗效果则大打折扣。
{"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}
引用次数: 0
Plasma genome-wide mendelian randomization identifies potentially causal genes in idiopathic pulmonary fibrosis. 血浆全基因组泯灭随机化确定了特发性肺纤维化的潜在致病基因。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-18 DOI: 10.1186/s12931-024-03008-5
Kun Zhang, Puyu Shi, Anqi Li, Jiejun Zhou, Mingwei Chen

Background: 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.

Methods: 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.

Results: 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, FDRSMR = 0.029; OR: 0.85, 95% CI: 0.78-0.92, FDRSMR = 0.043), and RIPK4 was positively associated with IPF risk (OR: 2.60, 95% CI: 1.64-4.12, FDRSMR = 0.031). cg00045227 (OR8U8, OR: 1.16, 95% CI: 1.08-1.24, FDRSMR = 0.010), cg00577578 (GBAP1, OR: 1.23, 95% CI: 1.12-1.36, FDRSMR = 0.014), cg14222479 (ARPM1, OR: 3.17, 95% CI: 1.98-5.08, FDRSMR = 0.001), and cg19263494 (PMF1, OR: 1.20, 95% CI: 1.10-1.30, FDRSMR = 0.012) were positively associated with the risk of IPF, whereas cg07163735 (MAPT, OR: 0.22, 95% CI: 0.11-0.45, FDRSMR = 0.013) was negatively correlated with the risk of IPF.

Conclusions: 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.

背景:特发性肺纤维化(IPF特发性肺纤维化(IPF)是一种复杂的肺部疾病,预后极差。现有治疗 IPF 的药物仍然不足。因此,仍有必要探索预防和治疗 IPF 的新药物靶点:我们纳入了血浆中基因、DNA甲基化和蛋白质的定量性状位点(QTL),以及 IPF 的汇总统计数据。位于基因 500 kb 范围内且与血浆暴露密切相关的基因变异被用作工具变量。血浆暴露与 IPF 之间的因果关系主要通过基于汇总数据的孟德尔随机(SMR)分析进行估计。还采用了其他五种 MR 方法和敏感性分析来验证 SMR 结果。QTL与IPF风险基因座之间的贝叶斯检验进一步加强了MR结果:结果:通过SMR分析、MR分析验证、敏感性分析和共定位分析,我们确定了与IPF有因果关系的3个基因和5个DNA甲基化位点。BTRC和LINC01252与IPF风险呈负相关(OR:0.30,95% CI:0.17-0.54,FDRSMR = 0.029;OR:0.85,95% CI:0.78-0.92,FDRSMR = 0.043),RIPK4 与 IPF 风险正相关(OR:2.60,95% CI:1.64-4.12,FDRSMR = 0.031)。cg00045227(OR8U8,OR:1.16,95% CI:1.08-1.24,FDRSMR = 0.010)、cg00577578(GBAP1,OR:1.23,95% CI:1.12-1.36,FDRSMR = 0.014)、cg14222479(ARPM1,OR:3.17,95% CI:1.98-5.08,FDRSMR = 0.001)和 cg19263494(PMF1,OR:1.20,95% CI:1.10-1.30,FDRSMR = 0.012)与 IPF 风险呈正相关,而 cg07163735(MAPT,OR:0.22,95% CI:0.11-0.45,FDRSMR = 0.013)与 IPF 风险呈负相关:该研究表明,由基因决定的 BTRC、RIPK4 和 LINC01252 基因的血浆水平,以及 cg00045227 (OR8U8)、cg00577578 (GBAP1)、cg07163735 (MAPT)、cg14222479 (ARPM1) 和 cg19263494 (PMF1) 的甲基化水平对 IPF 的风险有因果影响。
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引用次数: 0
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. 吸入二丙酸倍氯米松/富马酸福莫特罗/甘草酸铵与二丙酸倍氯米松/富马酸福莫特罗和安慰剂对慢性阻塞性肺病患者肺过度充气和运动耐力的影响:随机对照试验。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-17 DOI: 10.1186/s12931-024-02993-x
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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov (NCT05097014), registered 27th October 2021.

背景:二丙酸倍氯米松、富马酸福莫特罗和甘草酸铵(BDP/FF/G)三合一单吸入剂可用于慢性阻塞性肺病(COPD)的维持治疗。慢性阻塞性肺病的主要特征是肺过度充气和运动能力下降。TRIFORCE 旨在评估 BDP/FF/G 对慢性阻塞性肺病患者肺过度充气和运动能力的影响:这项双盲、随机、活性和安慰剂对照的交叉研究招募了年龄≥ 40 岁的慢性阻塞性肺病成人患者,他们都有过度充气和症状,正在接受单药或双药吸入维持性慢性阻塞性肺病治疗。在三个治疗期中,患者被随机分配接受 BDP/FF/G、BDP/FF 或安慰剂治疗,每个治疗期为 3 周,治疗期之间有 7-10 天的冲洗期。评估包括慢速吸气肺活量测定法(测定静息吸气容量 [IC])和恒定工作速率循环测力法(测定动态吸气容量和运动耐力时间)。主要目标是比较 BDP/FF/G 和 BDP/FF 与安慰剂在第 3 周的静息吸气容量。主要次要目标是比较 BDP/FF/G 和 BDP/FF 与安慰剂在第 3 周的动态 IC 和恒定工作速率循环测力过程中的运动耐力时间:结果:在 106 名随机患者中,95 人完成了研究。BDP/FF/G 和 BDP/FF 与安慰剂相比,静息 IC 调整后的平均差异分别为 315 毫升和 223 毫升(P在慢性阻塞性肺病患者中,BDP/FF/G 与安慰剂和 BDP/FF 相比,在静态和动态过度充气方面有显著的临床相关性改善,与安慰剂相比,在运动耐力方面也有改善:试验注册:ClinicalTrials.gov (NCT05097014),2021 年 10 月 27 日注册。
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引用次数: 0
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