Microbial Dysbiosis in Chronic Lung Allograft Dysfunction

项目概要： 肺移植是治疗终末期肺部疾病的唯一有效方法， 肺纤维化、COPD、囊性纤维化和肺动脉高压。但长期 肺移植受者（LTR）的存活率是所有器官移植中最低的， 中位生存期为6年。大约50%的LTR在5年内发生慢性排斥反应 移植后，一种称为慢性肺移植物功能障碍（CLAD）的综合征。包覆 发病机制知之甚少。我们和其他人已经表明，肺生态失调（破坏 微生物群稳态）与CLAD密切相关，尽管迄今尚不清楚是否 生态失调是CLAD的原因或结果。不像肠道生态失调，这是一个既定的风险， 慢性炎症性疾病;肺生态失调的作用及其与CLAD的联系机制 尚待确定，这是一个重大的知识差距。我们的目标是使用 纵向方法来定义在CLAD发作之前的致病性肺微生物组， 研究微生物群诱导的纤维化增加CLAD易感性的机制。 我们的假设是，肺生态失调抑制了上皮细胞自噬清除促纤维化因子， 细胞因子以IL-33依赖的方式，从而增加纤维化和CLAD的风险。 SA 1：研究IL-33阻断在减弱肺生态失调相关纤维化中的作用 和CLAD。SA 2：阐明IL-33的作用机制 自噬的调节与肺中的促纤维化反应有关。SA 3：确定 人肺生态失调、IL-33与CLAD易感性的关系。完成 拟议的研究将（a）确定肺中气道微生物生态失调之间的机制联系， 移植受体对失调的上皮反应和CLAD的反应;（B）提供概念验证 IL-33阻断可以有利地调节微生物组介导的促纤维化反应， 到CLAD。(c)识别特定的气道微生物组特征，以识别那些有CLAD风险的人。

PROJECT SUMMARY: Lung transplant is the only curative treatment for end stage lung diseases such as idiopathic pulmonary fibrosis, COPD, cystic fibrosis and pulmonary hypertension. However, long-term survival of lung transplant recipients (LTRs) is the lowest among all organ transplantations with a median survival of 6 years. Approximately 50% of LTR’s develop chronic rejection within 5 years post-transplantation, a syndrome referred to as chronic lung allograft dysfunction (CLAD). CLAD pathogenesis is poorly understood. We and others have shown that lung dysbiosis (disruption of microbiota homeostasis) is strongly associated with CLAD, although to date it is unclear if dysbiosis is the cause or effect of CLAD. Unlike, gut dysbiosis which is an established risk for chronic inflammatory diseases; the role of lung dysbiosis and the mechanisms linking it to CLAD remain to be determined, representing a critical knowledge gap. Our objectives are to use a longitudinal approach to define the pathogenic lung microbiome that predates CLAD onset and investigate mechanisms for microbiome-induced fibrogenesis that increase CLAD susceptibility. Our hypothesis is that lung dysbiosis inhibits epithelial autophagic clearance of pro-fibrotic cytokines in an IL-33 dependent manner, thereby augmenting fibrogenesis and risk for CLAD. SA1: To investigate the role of IL-33 blockade in attenuation of lung dysbiosis related fibrogenesis and CLAD in a murine lung transplant model. SA2: To elucidate the mechanisms of IL-33 regulation of autophagy that are linked to pro-fibrotic responses in the lung. SA3: To determine the relationship between human lung dysbiosis, IL-33 and CLAD susceptibility. Completion of the proposed studies will (a) define the mechanistic link between airway microbial dysbiosis in lung transplant recipients to dysregulated epithelial responses and CLAD; (b) provide proof-of-concept that IL-33 blockade can favorably modulate microbiome mediated pro-fibrotic response leading to CLAD. (c) Identify specific airway microbiome signatures that identify those at risk for CLAD.