Fungal Translocation in Chronic Obstructive Pulmonary Disease

慢性阻塞性肺疾病中的真菌移位

• 批准号: 10610446
• 负责人: JESSICA BON
• 金额: $ 78.56万
• 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/10610446
• 关键词: Acute; Air; Antiinflammatory Effect; Apical; Attenuated; Bacteria; Bacterial Translocation; Binding; CCL2 gene; CCL20 gene; CXCL10 gene; CXCL5 gene; Cell Wall; Cells; Cellular Structures; Chronic Obstructive Pulmonary Disease; Circulation; Clinical; Clinical Trials; Data; Dendritic Cells; Disease; Disease Marker; Disease Outcome; Disease Progression; EphA2 Receptor; Epithelial Cells; Epithelium; 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; Liquid substance; Lung; Macrophage; Macrophage Activation; Mannitol; Measures; Mediating; Mediation; Mediator; 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; microbial; microbial products; 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 吸烟是慢性阻塞性肺疾病（COPD）的主要因素，其他可能的因素可能 有助于疾病发病机理，因为只有一部分吸烟者会出现与组织缺氧相关的COPD。 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 一旦循环，微生物或微生物产物的移动， 这些微生物产物可能会导致免疫细胞激活或直接肺损伤，增加炎症和 COPD患者的肺功能下降。 Bactteria的易位，我们有原始数据表明真菌组成发生在吸烟者中 并可能有助于COPD发病机理。 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，症状和疾病的离开相关。 体外BDG增加了参与参与的炎症细胞因子的肺肺上皮细胞表达 在这个项目中，我们将测试肠道上皮屏障完整性的总体高度假设 COPD患者导致真菌微生物易位，导致肺功能，更糟 呼吸道通过特殊的免疫细胞激活和直接的肺致病作用 评估由乳乳糖/甘露醇差异测量的肠道上皮屏障完整性之间的关系 糖吸收测试，肺功能，呼吸道病（症状，恶化）和循环的BDG水平 在与COPD的当前和前吸烟者中，AIM 2将决定循环 BDG水平，免疫细胞激活，前瞻性加重以及肺功能的两年变化，症状， COPD中肺气肿和气道的CT指数。 表达和分泌的蛋白质水平通过与肺脊柱细胞细胞模式识别识别接收 - 1和Epha2体外人支气管上皮细胞中 烟雾3还将调查BDG是否对细胞因子表达和分泌蛋白水平的影响 通过二甲双胍的治疗减弱。 微生物易位在COPD发病机理中的作用，并将为将来的清除试验奠定基础 通过改善肠道上皮屏障功能，阻止BDG的动作或 调节BDG的下游效应为COPD中新型的进近治疗。