Fungal Translocation in Chronic Obstructive Pulmonary Disease

慢性阻塞性肺疾病中的真菌移位

基本信息

批准号：
10434243
负责人：
JESSICA BON
金额：
$ 77.57万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434243
关键词：
Acute Air Antiinflammatory Effect Apical Attenuated Bacteria Bacterial Translocation Binding Blood Circulation CCL2 gene CCL20 gene CXCL10 gene CXCL5 gene Cell Wall Cells Cellular Structures Chronic Obstructive Pulmonary Disease Clinical Clinical Trials Data Dendritic Cells Disease Disease Marker Disease Outcome Disease Progression EphA2 Receptor Epithelial Epithelial Cells Exercise Exposure to Foundations Frequencies Fungal Components Future Human Hypoxia IL8 gene Immune Immune response Immunoassay Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Interleukin-6 Intestinal Mucosa Intestinal permeability Intestines Lactulose Lead Liquid substance Lung Macrophage Activation Mannitol Measures Mediating Mediation Mediator of activation protein Metformin Microbe Molecular Movement Mycoses Organism Outcome Pathogenesis Pathogenicity Patients Pattern Pattern recognition receptor Peripheral Physical activity Play Polysaccharides Protein Secretion Proteins Pulmonary Emphysema Respiratory Signs and Symptoms Rest Reverse Transcriptase Polymerase Chain Reaction Risk Factors Role Severity of illness Small Interfering RNA Smoker Smoking Symptoms TNF gene Testing Tissues Validation Western Blotting absorption bronchial epithelium chest computed tomography cigarette smoke cohort cytokine dectin 1 experimental study exposure to cigarette smoke follow-up former smoker functional decline gastrointestinal epithelium gut-lung axis immune activation improved indexing insight knock-down laminaran lung injury mRNA Expression macrophage microbial novel strategies novel therapeutic intervention novel therapeutics pathogen polyglucosan prospective pulmonary function pulmonary function decline respiratory respiratory morbidity small molecule inhibitor sugar targeted treatment

项目摘要

PROJECT SUMMARY Although smoking is a leading risk factor for chronic obstructive pulmonary disease (COPD), other factors likely contribute to disease pathogenesis since only a subset of smokers develop COPD. Tissue hypoxia related to acute exacerbations or physical activity impairs gut epithelial barrier function in COPD and may result in microbial translocation, or movement of microbes or microbial products across the intestinal mucosa. Once in circulation, these microbial products may cause immune cell activation or direct lung injury, augmenting inflammation and lung function decline in patients with COPD. Although studies of microbial translocation have largely focused on the translocation of bacteria, we have preliminary data suggesting that fungal translocation occurs in smokers and may contribute to COPD pathogenesis. We show that 1,3 beta-d-glucan (BDG), a pattern associated molecular pattern that is a major polysaccharide component of the fungal cell wall, is elevated in COPD patients in the absence of invasive fungal infection and correlates with lung function, symptoms, and exacerbations. In vitro, BDG increases lung epithelial cell expression of inflammatory cytokines involved in the pathogenesis of COPD. With this project, we will test the overarching hypothesis that impaired gut epithelial barrier integrity in COPD patients leads to fungal microbial translocation that contributes to lung function decline and worse respiratory morbidity through heightened immune cell activation and direct lung pathogenic effects. Aim 1 will assess the relationship between gut epithelial barrier integrity measured by the lactulose/mannitol differential sugar absorption test, lung function, respiratory morbidity (symptoms, exacerbations), and circulating BDG levels in a cohort of current and former smokers with COPD. Aim 2 will determine the association between circulating BDG levels, immune cell activation, prospective exacerbations, and two-year change in lung function, symptoms, and CT indices of emphysema and airways in COPD. Aim 3 will determine whether BDG increases cytokine expression and secreted protein levels by binding to the lung epithelial cell pattern recognition receptors Dectin- 1 and EphA2 in human bronchial epithelial cells in vitro, and if this effect is potentiated by co-exposure to cigarette smoke. Aim 3 will also investigate if BDG effects on cytokine expression and secreted protein levels are attenuated by treatment with metformin. At the completion of this project, we will have gained critical insight into the role of microbial translocation in COPD pathogenesis and will have built the foundation for future clinical trials targeting the gut-lung axis by either improving gut epithelial barrier function, blocking BDG’s actions, or modulating BDG’s downstream effects as a novel approach to therapy in COPD.

项目概要尽管吸烟是慢性阻塞性肺病 (COPD) 的主要危险因素，但其他因素也可能由于只有一小部分吸烟者会出现与慢性阻塞性肺病相关的组织缺氧。急性加重或体力活动会损害 COPD 患者的肠道上皮屏障功能，并可能导致微生物微生物或微生物产物一旦进入循环，就会发生易位或移动。这些微生物产物可能会导致免疫细胞激活或直接肺部损伤，加剧炎症和尽管微生物易位的研究主要集中在慢性阻塞性肺病患者的肺功能下降。细菌易位，我们有初步数据表明吸烟者发生真菌易位我们发现 1,3 β-d-葡聚糖 (BDG) 可能与 COPD 发病机制有关。作为真菌细胞壁主要多糖成分的分子模式在慢性阻塞性肺病患者中升高在没有侵袭性真菌感染的情况下，并且与肺功能、症状和病情恶化相关。在体外，BDG 增加肺上皮细胞炎症细胞因子的表达，参与炎症的发病机制。通过这个项目，我们将测试肠道上皮屏障完整性受损的总体假设。慢性阻塞性肺病患者会导致真菌微生物易位，导致肺功能下降甚至更糟目标 1 将通过哮喘免疫细胞激活和直接肺部致病作用而导致呼吸道疾病。评估通过乳果糖/甘露醇差异测量的肠上皮屏障完整性之间的关系糖吸收测试、肺功能、呼吸道疾病（症状、加重）和循环 BDG 水平目标 2 将确定患有慢性阻塞性肺病 (COPD) 的当前吸烟者和曾经吸烟者之间的关联。 BDG 水平、免疫细胞激活、预期恶化以及肺功能、症状的两年变化，目标 3 中 COPD 肺气肿和气道的 CT 指数将决定 BDG 是否增加细胞因子。通过与肺上皮细胞模式识别受体 Dectin- 结合来调节表达和分泌蛋白水平 1 和 EphA2 在体外人支气管上皮细胞中的作用，并且如果同时接触香烟会增强这种作用目标 3 还将研究 BDG 对细胞因子表达和分泌蛋白水平的影响是否存在。通过二甲双胍治疗减弱。在该项目完成后，我们将获得对以下方面的重要见解：微生物易位在慢性阻塞性肺病发病机制中的作用，将为未来的临床试验奠定基础通过改善肠上皮屏障功能、阻断 BDG 的作用或调节 BDG 的下游效应作为 COPD 的一种新治疗方法。