Fungal Translocation in Chronic Obstructive Pulmonary Disease

慢性阻塞性肺疾病中的真菌移位

• 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
• 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

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.

项目摘要 尽管吸烟是慢性阻塞性肺疾病（COPD）的主要危险因素，但其他可能的因素可能 由于只有一部分吸烟者发展COPD，因此有助于疾病发病机理。组织缺氧与 急性加重或体育锻炼会损害COPD中的肠道上皮屏障功能，可能导致微生物 易位，或微生物或微生物产物在整个肠粘膜上的运动。一旦流通， 这些微生物产物可能会引起免疫细胞激活或直接肺损伤，增强感染和 COPD患者的肺功能下降。尽管微生物易位的研究主要集中在 细菌的易位，我们有初步数据，表明真菌易位发生在吸烟者中 并可能有助于COPD发病机理。我们表明1,3β-D-Glucan（BDG），一种相关的模式 COPD患者的分子模式是真菌细胞壁的主要多糖成分的升高 在没有侵入性真菌感染的情况下，与肺功能，症状和恶化有关。 体外BDG增加了参与参与的炎症细胞因子的肺上皮细胞表达 COPD。通过这个项目，我们将检验总体假设，即肠道上皮屏障完整性受损 COPD患者导致真菌微生物易位，导致肺功能下降，更糟 通过增强免疫细胞激活和直接肺致病作用，呼吸发病率。目标1意志 评估乳糖/甘露醇差异测量的肠道上皮屏障完整性 糖抽象测试，肺功能，呼吸道发病率（症状，恶化）和循环的BDG水平 与COPD的当前和前吸烟者队列中。 AIM 2将确定循环之间的关联 BDG水平，免疫电池激活，前瞻性加重以及肺功能的两年变化，符号， COPD中肺气肿和气道的CT指数。 AIM 3将确定BDG是否增加了细胞因子 通过与肺上皮细胞模式识别受体结合，表达和分泌的蛋白质水平 1和Epha2体外人支气管上皮细胞中 抽烟。 AIM 3还将研究BDG是否对细胞因子表达和分泌蛋白水平的影响是 用二甲双胍治疗减弱。该项目完成时，我们将获得关键的了解 微生物易位在COPD发病机理中的作用，并将为将来的临床试验奠定基础 通过改善肠道上皮屏障功能，阻止BDG的动作或 调节BDG的下游效应是COPD中一种新型治疗方法。