HIV, Alcohol and TB Pleurisy

描述（由申请人提供）：众所周知，酗酒和人类免疫缺陷病毒（HIV）都会损害对感染的正常免疫反应。胸膜肺结核是一个主要的健康问题，特别是在发展中国家，常见于艾滋病患者或酗酒者。酒精引起的组织损伤和细胞应激进一步损害了正常的保护反应。血红素加氧酶（HO）是一种微粒体应激诱导酶，通过释放其代谢产物铁蛋白、胆红素和一氧化碳来保护细胞。在我们的初步研究中，我们证明在胸膜结核中，HO的诱导型（HO-1）被酒精抑制。基于背景信息和我们的初步数据，我们假设：慢性酒精滥用导致胸膜肺结核患者血红素加氧酶-1 （HO-1）酶表达抑制，导致细胞应激增加，肉芽肿形成不良和分枝杆菌传播。我们将在以下具体目标中评估我们的假设：具体目标1：评估印度昌迪加尔胸膜结核患者中酗酒和艾滋病毒状况的患病率，并评估这些患者胸膜炎症细胞和液体中HO-1及其代谢终产物是否减少。特异性目的2：评估慢性酒精给药胸膜结核小鼠是否导致炎症细胞和常驻细胞中HO-1表达降低、肉芽肿形成减少和分枝杆菌传播增加。具体目标3。评估酒精是否通过HO-1介导的机制改变了分枝杆菌诱导的胸膜间皮通透性和屏障功能。解决这些具体目标将使我们能够在资源贫乏的社会中收集重要信息，并更好地了解酒精在增加胸膜肺结核易感性方面的作用。

DESCRIPTION (provided by applicant): Alcohol abuse and the Human immunodeficiency virus (HIV) are both known to compromise normal immune responses to infections. Pleuropulmonary tuberculosis is a major health problem, particularly in developing countries and is commonly found in patients who have AIDS or those who abuse alcohol. Alcohol-induced tissue injury and cellular stress further compromise normal protective responses. Heme oxygenase (HO) is a microsomal stress-induced enzyme that is cytoprotective through the release of its metabolic products, ferritin, bilirubin and carbon monoxide. In our preliminary studies, we demonstrate that in pleural tuberculosis, the inducible form of HO (HO-1) in inhibited by alcohol. Based on background information and our preliminary data, we hypothesize that: Chronic alcohol abuse causes inhibition of heme oxygenase -1 (HO-1) enzyme expression that leads to increased cellular stress, poor granuloma formation and dissemination of mycobacteria in patients with pleuropulmonary tuberculosis. We will evaluate our hypothesis in the following specific aims: Specific Aim 1: To evaluate the prevalence of alcohol abuse and HIV status in patients with pleural tuberculosis in Chandigarh, India and to evaluate if these patients have decreased HO-1 and its metabolic end products in pleural inflammatory cells and fluids. Specific Aim 2: To evaluate if chronic alcohol administration to mice with pleural TB causes decreased HO-1 expression, in inflammatory and resident cells, decreased granuloma formation and increased dissemination of mycobacteria. Specific Aim 3. To evaluate if alcohol alters mycobacteria-induced pleural mesothelial permeability and barrier function in vitro through HO-1- mediated mechanisms. Addressing these specific aims will allow us to collect important information in a resource poor society, and better understand the role of alcohol in increasing susceptibility to pleuropulmonary tuberculosis.