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 虽然吸烟是慢性阻塞性肺疾病（COPD）的主要危险因素，但其他因素可能 这可能有助于疾病的发病机制，因为只有一部分吸烟者会发展为COPD。组织缺氧相关 急性加重或体力活动损害COPD患者的肠上皮屏障功能，并可能导致微生物 微生物或微生物产物穿过肠粘膜的移位或移动。一旦进入流通， 这些微生物产物可引起免疫细胞活化或直接肺损伤，增加炎症， COPD患者肺功能下降。虽然微生物易位的研究主要集中在 我们有初步的数据表明，吸烟者中发生真菌易位 并可能导致COPD发病。我们发现，1，3 β-D-葡聚糖（BDG），一种与 作为真菌细胞壁的主要多糖成分的分子模式在COPD患者中升高 在没有侵袭性真菌感染的情况下，与肺功能、症状和恶化相关。在 在体外，BDG增加了肺上皮细胞中参与发病机制的炎性细胞因子的表达， 慢性阻塞性肺病在这个项目中，我们将测试总体假设，即肠道上皮屏障完整性受损， COPD患者导致真菌微生物易位，导致肺功能下降和恶化 呼吸道疾病通过增强免疫细胞激活和直接肺部致病作用。目标1将 评估通过乳果糖/甘露醇差异测量的肠上皮屏障完整性与 糖吸收试验、肺功能、呼吸系统发病率（症状、加重）和循环BDG水平 在一组患有COPD的吸烟者和既往吸烟者中。目标2将确定循环之间的关联 BDG水平、免疫细胞活化、预期加重和肺功能、症状的两年变化， COPD肺气肿及气道CT指标。目的3将确定BDG是否增加细胞因子 通过结合肺上皮细胞模式识别受体Dectin， 1和EphA 2在体外人支气管上皮细胞中的作用，以及这种作用是否通过共暴露于香烟而增强 抽烟目标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 通过二甲双胍治疗而减弱。在这个项目完成后，我们将获得关键的洞察力， 微生物易位在COPD发病机制中的作用，并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治疗的新方法。