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.

项目总结 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 由于只有一小部分吸烟者会患上慢性阻塞性肺疾病，导致了疾病的发生。与组织缺氧有关的 急性加重或体力活动损害COPD患者肠道上皮屏障功能，并可能导致微生物 移位，即微生物或微生物产品在肠道粘膜上的移动。一旦流通起来， 这些微生物产物可能导致免疫细胞激活或直接肺损伤，加剧炎症和 慢性阻塞性肺疾病患者肺功能下降。尽管对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身上。 可能参与了COPD的发病机制。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组分的分子模式在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……里面 补肾活血方在体外增加肺上皮细胞炎性细胞因子的表达，参与糖尿病的发病机制。 慢性阻塞性肺疾病（慢阻肺）。在这个项目中，我们将检验主要的假设，即肠道上皮屏障完整性受损 慢性阻塞性肺疾病患者导致真菌微生物易位，导致肺功能下降和恶化 通过增强免疫细胞活性和直接的肺部致病作用引起的呼吸道疾病。目标1将 用乳果糖/甘露醇差值评价肠上皮屏障完整性的关系 糖吸收试验、肺功能、呼吸道发病率(症状、加重)和循环BDG水平 在一组患有慢性阻塞性肺病的现任和前任吸烟者中。目标2将确定循环之间的关联 血糖水平，免疫细胞激活，预期恶化，以及两年来肺功能，症状， COPD患者肺气肿和呼吸道的CT指标。目标3将确定BDG是否会增加细胞因子 通过与肺上皮细胞模式识别受体Dectin结合来表达和分泌蛋白质水平 1和EphA2在体外培养的人支气管上皮细胞中的表达，以及香烟联合暴露是否增强这一效应 烟。AIM 3还将调查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变弱。在这个项目完成后，我们将获得对 微生物易位在COPD发病机制中的作用，将为未来的临床试验奠定基础 通过改善肠道上皮屏障功能，阻断BDG的作用，或 调节BDG的下游效应作为COPD治疗的新方法。