HO-1 and granuloma formation in TB pleurisy

描述（由申请人提供）：结核病是艾滋病患者的地方病，具有侵袭性，肉芽肿内分枝杆菌定位不良，广泛感染。肉芽肿是来源于循环外周血单核细胞（PBMC）的富含单核细胞的细胞集合。针对病原体的经典反应是细胞保护基因的表达，包括血红素加氧酶-1（HO-1），其允许调节炎症反应以及抑制细胞凋亡。单核细胞通过C-C趋化因子（主要是单核细胞趋化蛋白-1，MCP- 1）和单核细胞表达CCR 2受体的相互作用被募集到结核感染部位。这是该提议的假设，即在募集的单核细胞-巨噬细胞中HO-1表达代表参与胸膜结核中有效的抗分枝杆菌宿主防御的关键调节事件。HO-1耗竭增强胸膜巨噬细胞凋亡，并通过引起导致细胞凋亡的信号传导途径的改变和通过改变外周血单核细胞（PBMC）和胸膜巨噬细胞（PM）上CCR 2的体内表达而阻碍分枝杆菌清除，从而导致不良肉芽肿形成。我们在HO-1 -/-和HO-1 +/+小鼠中建立了胸膜结核模型，以评估HO-1介导的PBMC和胸膜巨噬细胞（PM）上CR2受体的调节。我们将评估我们的假设在我们的胸膜结核模型在体内以及体外PBMC和引发胸膜巨噬细胞。我们的具体目标是：具体目标1：在TB胸膜炎的鼠模型和体外评估来自用H37 Rv治疗的对照HO-1 +/+和HO-1 -/-小鼠的外周血单核细胞和胸膜巨噬细胞中的基因表达谱。具体目的#2：评估在结核性胸膜炎的胸膜间隙中肉芽肿形成期间HO-1在外周血单核细胞和胸膜巨噬细胞凋亡中的调节作用。具体目标3：探讨HO-1在结核性胸膜炎胸膜腔肉芽肿形成过程中对外周血单核细胞和胸膜巨噬细胞CCR 2表达的调节作用。了解HO-1介导的巨噬细胞募集、滞留和凋亡调节的机制，导致肉芽肿形成，对于患者中观察到的胸膜肺结核的病理生理学至关重要，并将有助于开发增强宿主防御反应的治疗方式。公共卫生相关性：了解HO-1介导的巨噬细胞募集、滞留和凋亡调节的机制，导致肉芽肿形成，对于患者中观察到的胸膜肺结核的病理生理学至关重要，并将有助于开发增强宿主防御反应的治疗方式。

DESCRIPTION (provided by applicant): Tuberculosis is endemic among patients with AIDS and follows an aggressive course with poor localization of mycobacteria into granuloma and widespread infection. Granulomas are monocyte rich collections of cells which derive from the circulating peripheral blood monocyte (PBMC). A classical response against pathogens is the expression of cytoprotective genes including Heme-oxygenase-1 (HO-1) which allows for a regulated inflammatory response as well as inhibits apoptosis of cells. Monocytes are recruited to the site of tuberculous infection by the interaction of C-C chemokines, (mainly monocyte chemoattractant protein-1, MCP- 1) and monocyte expression of the CCR2 receptor. It is the hypothesis of this proposal that HO-1 expression in recruited monocyte-macrophages represents a critical regulatory event involved in effective anti-mycobacterial host defense in pleural tuberculosis. HO-1 depletion enhances pleural macrophage apoptosis and impedes mycobacterial clearance by causing alterations in the signaling pathways leading to apoptosis and by altering the in vivo expression of CCR2 on the peripheral blood mononuclear cells (PBMC) and pleural macrophage (PM) leading to poor granuloma formation. We have developed a model of pleural tuberculosis in HO-1 -/- and HO-1 +/+ mice to evaluate the HO-1 mediated regulation of the CR2 receptor on PBMC and pleural macrophages (PM). We will evaluate our hypothesis in our model of pleural tuberculosis in vivo as well as in vitro in PBMC and elicited pleural macrophages. Our specific aims are: Specific aim #1: To evaluate gene expression profiles in peripheral blood monocytes and pleural macrophages from control HO-1 +/+ and HO-1 -/- mice, treated with H37Rv, in a murine model of TB pleurisy and in vitro Specific aim #2: To evaluate the regulatory role of HO-1 in apoptosis of peripheral blood monocytes and pleural macrophages during granuloma formation in the pleural space in tuberculous pleurisy. Specific aim #3: To evaluate the regulatory role of HO-1 in the expression of CCR2 on peripheral blood monocytes and pleural macrophages during granuloma formation in the pleural space in tuberculous pleurisy. Understanding the mechanisms underlying HO-1 mediated regulation of macrophage recruitment, retention and apoptosis, leading to granuloma formation is critical to the pathophysiology of pleuro-pulmonary tuberculosis seen in patients and will help develop therapeutic modalities that augment host-defense responses. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms underlying HO-1 mediated regulation of macrophage recruitment, retention and apoptosis, leading to granuloma formation is critical to the pathophysiology of pleuro-pulmonary tuberculosis seen in patients and will help develop therapeutic modalities that augment host-defense responses.