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.
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