ALCOHOL INDUCED IMMUNOMODULATION--RETROVIRAL CARDIOPATH

心肌病和左心室功能障碍在艾滋病患者或长期饮酒人群中很普遍。然而，人们对逆转录病毒感染加上酒精对心脏病的综合影响几乎一无所知。我们的小鼠逆转录病毒感染模仿了HIV感染期间发现的许多细胞因子失调，促进了心脏毒性的炎症损伤。我们发现，饮酒加剧了小鼠逆转录病毒感染引起的许多免疫、氧化和营养缺陷。我们发现酒精+逆转录病毒暴露特别有毒，增加Th2和减少Th1细胞因子，显著降低心脏维生素E，增加心脏脂质氧化，协同促进柯萨奇B3感染引起的严重心脏损伤。我们的总体假设是乙醇+逆转录病毒感染的组合诱导免疫功能障碍和氧化增加心血管疾病。这些作用应该促进心营养病原体的生长和发病。这一假设将在逆转录病毒和/或乙醇暴露期间用柯萨奇B感染小鼠进行调查。左心室功能将通过室内导管在体内定量测定，以确定心室功能障碍和表征酒精的影响。我们将确定由酒精和/或逆转录病毒暴露引起的炎症反应对心肌缺血事件和梗死的贡献。我们将断言涉及PMNs的免疫机制在可卡因和逆转录病毒暴露期间放大缺血性损伤。我们将评估白细胞粘附和定位，血小板-白细胞相互作用，以及用药物阻断这些细胞的功能，以了解它们在可卡因和/或逆转录病毒暴露诱导的缺血和心脏泵功能障碍中的作用。我们将断言酒精暴露在逆转录病毒感染之前和之后的心脏毒性作用。我们的模型研究将增加对酒精+逆转录病毒诱导的心脏病理免疫功能障碍病因学的理解。我们将限制逆转录病毒感染和酒精暴露对心脏的有害影响，我们已经证实的方法可以防止许多细胞因子失调和心脏氧化损伤：t细胞受体Vbeta 8.1，多种抗氧化剂和维生素E补充。我们假设我们的治疗将限制细胞因子失调，从而限制逆转录病毒感染的酒精暴露小鼠的心脏毒性。这些研究可以为它们在酗酒、hiv感染患者中减少心脏病的应用提供基础。

Cardiomyopathy and left ventricular dysfunction are prevalent in people with AIDS or chronic alcohol use. However almost nothing is known of the combined effects of retroviral infection plus alcohol on heart disease. Our murine retrovirus infection mimics much of the cytokine dysregulation found during HIV infection, prompting inflammatory damage for cardiac toxicity. We found that alcohol consumption exacerbated many immune, oxidative, and nutritional defects due to murine retrovirus infection. We found that alcohol + retrovirus exposure was particularly toxic, increasing Th2 and reducing Th1 cytokines, dramatically lowering cardiac vitamin E, increasing oxidation of cardiac lipids and synergistically promoting severe heart damage due to Coxsackie B3 infection. Our overall hypothesis is that the combination of ethanol + retroviral infection induces immune dysfunction and oxidation for increased cardiovascular disease. These effects should promote growth and pathogenesis of cardiotrophic pathogens. This hypothesis will be investigated using Coxsackie B infection of mice during retrovirus and/or ethanol exposure. Left ventricular function will be quantitated in vivo with interventricular catheter to define the ventricular dysfunction and characterize the effects of alcohol. We will determine the contribution of the inflammatory response, induced by alcohol and/or retroviral exposure, to myocardial ischemic events and infarctions. We will assert the immune mechanisms involving PMNs in amplifying ischemic injury during cocaine plus retroviral exposure. We will assess leukocyte adhesion and localization, platelet-leukocyte interactions, and blocking these cells' function with drugs to understand their role in ischemia and heart pump dysfunction induced by cocaine and/or retrovirus exposure. We will assert the cardiotoxic effects of alcohol exposure prior to as well as post retrovirus infection. Our model studies will increase understanding of etiology of alcohol + retrovirus-induced immune dysfunction in cardiac pathology. We will limit the deleterious cardiac effects of retroviral infection and alcohol exposure with our proven methods that prevented much of the cytokine dysregulation and oxidative damage to the heart: T-cell receptor Vbeta 8.1, multiple antioxidant, and vitamin E supplementation. We hypothesize that our treatments will restrict cytokine dysregulation and thus cardiotoxicity in retrovirally-infected, alcohol-exposed mice. Such studies could provide the basis for their application to reduce heart disease in alcohol-abusing, HIV-infected patients.