Microbial Dysbiosis in Chronic Lung Allograft Dysfunction

慢性同种异体肺移植功能障碍中的微生物失调

• 批准号: 10670401
• 负责人: Nirmal S Sharma
• 金额: $ 51.91万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670401
• 关键词: Acceleration; Attenuated; Autophagocytosis; BCL2 gene; Bacteroidetes; Biological Markers; Biopsy Specimen; Bronchiolitis; Bronchoalveolar Lavage; Chronic; Chronic Obstructive Pulmonary Disease; Coculture Techniques; Cystic Fibrosis; Data; Epithelial Cells; Epithelium; Exposure to; Fibroblasts; Fibrosis; Firmicutes; Functional disorder; Gelatinase B; Goals; Graft Rejection; Homeostasis; Human; Impairment; In Vitro; Knock-out; Knowledge; Link; Longitudinal Studies; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Measures; Mediating; Modeling; Mus; Organ Transplantation; Pathogenesis; Pathogenicity; Patient-Focused Outcomes; Predisposition; Prevotella melaninogenica; Proteins; Proteobacteria; Pseudomonas aeruginosa; Pulmonary Hypertension; Regulation; Risk; Role; Solid; Specimen; Streptococcus pneumoniae; Syndrome; TLR4 gene; Testing; Therapeutic; Toll-like receptors; Transforming Growth Factor beta; Transplant Recipients; adjudication; attenuation; biological adaptation to stress; bronchial epithelium; chronic inflammatory disease; cohort; curative treatments; dysbiosis; epithelial injury; fibrogenesis; gut dysbiosis; idiopathic pulmonary fibrosis; improved; in vivo; inhibition of autophagy; intraperitoneal; loss of function; lung allograft; lung microbiome; machine learning algorithm; microbial; microbial signature; microbiome; microbiome signature; microbiota; mouse model; novel; post-transplant; profibrotic cytokine; rRNA Genes; receptor; respiratory; respiratory microbiome; respiratory pathogen; response; spatiotemporal; transplant model

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.

项目总结： 肺移植是特发性等终末期肺部疾病的唯一根治方法。 肺纤维化、慢性阻塞性肺疾病、囊性纤维化和肺动脉高压。然而，从长远来看， 肺移植受者(Ltrs)的存活率是所有器官移植患者中最低的。 中位生存期6年。约50%的移植肾移植患者在5年内出现慢性排斥反应 移植后，一种被称为慢性肺移植功能障碍(CLAD)的综合征。穿着的 发病机制尚不清楚。我们和其他人已经证明，肺的生物失调(破坏 微生物区系动态平衡)与包衣密切相关，尽管到目前为止还不清楚 生物失调是包衣的原因或结果。与之不同的是，肠道生物失调是一种既定的风险 慢性炎症性疾病；肺生态失调的作用及其与包膜的联系机制 仍然有待确定，这是一个严重的知识差距。我们的目标是使用 用纵向方法确定包膜发病前和发病前的致病肺微生物群 研究微生物组诱导的纤维形成增加包膜易感性的机制。 我们的假设是，肺的生物失调抑制了促纤维化的上皮自噬清除 细胞因子以IL-33依赖的方式，从而增加纤维化形成和包裹体的风险。 SA1：探讨IL-33拮抗剂在减轻肺生态失调相关纤维化中的作用 穿着小鼠肺移植模型。SA2：阐明IL-33的作用机制 自噬的调节与肺内的促纤维化反应有关。SA3：确定 人肺微生态失调、IL-33与包膜易感性的关系已完成的 拟议的研究将(A)确定肺部呼吸道微生物失调之间的机制联系。 移植受者对失调的上皮反应和包裹体；(B)提供概念验证 阻断IL-33可以有利地调节微生物组介导的促纤维化反应 穿上衣服。(C)确定特定的呼吸道微生物群特征，以确定那些有感染衣物风险的人。

项目成果

IL-33 mediates Pseudomonas induced airway fibrogenesis and is associated with CLAD.

• DOI: 10.1016/j.healun.2022.09.018
• 发表时间: 2022-10
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: Mudassir Meraj Banday;S. Rao;S. Shankar;M. Khanday;J. Finan;Edward O'Neill;A. Coppolino;A. Seyfang;Archit Kumar;D. Rinewalt;H. Goldberg;A. Woolley;H. Mallidi;G. Visner;A. Gaggar;K. Patel;N. Sharma