ALCOHOL INDUCED IMMUNOMODULATION--RETROVIRAL CARDIOPATH

酒精诱导的免疫调节——逆转录病毒心脏病

• 批准号: 6352194
• 负责人: RONALD Ross WATSON
• 金额: $ 6.63万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-03 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6352194
• 关键词: Coxsackievirus; T cell receptor; alcoholism /alcohol abuse; antioxidants; cardiotoxin; cardiovascular infection; cytokine; disease /disorder etiology; disease /disorder proneness /risk; hypertrophic myocardiopathy; immunomodulators; immunoregulation; inflammation; laboratory mouse; murine AIDSs; myocardial ischemia /hypoxia; nonhuman therapy evaluation; oxidative stress; oxidized lipid; pathologic process; tocopherols; virus infection mechanism; vitamin therapy

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.

心肌病和左心功能不全在艾滋病或长期饮酒的人中很常见。然而，关于逆转录病毒感染和酒精对心脏病的综合影响，人们几乎一无所知。我们的小鼠逆转录病毒感染模拟了HIV感染期间发现的大部分细胞因子失调，促使心脏毒性的炎性损害。我们发现，饮酒加剧了由于小鼠逆转录病毒感染而导致的许多免疫、氧化和营养缺陷。我们发现酒精+逆转录病毒暴露具有特别的毒性，增加Th2和减少Th1细胞因子，显著降低心脏维生素E，增加心脏脂质的氧化，并协同促进由于柯萨奇B3感染而造成的严重心脏损害。我们的总体假设是，乙醇+逆转录病毒感染的组合会导致免疫功能障碍和氧化，从而增加心血管疾病。这些作用应该促进心脏营养病原体的生长和致病。这一假说将通过小鼠在逆转录病毒和/或酒精暴露期间感染柯萨奇B病毒来进行研究。左心功能将用室间导管进行活体定量，以确定心功能不全，并表征酒精的影响。我们将确定酒精和/或逆转录病毒暴露引起的炎症反应对心肌缺血事件和心肌梗死的贡献。我们将断言涉及PMN的免疫机制在可卡因和逆转录病毒暴露期间放大缺血损伤。我们将评估白细胞的黏附和定位，血小板与白细胞的相互作用，以及用药物阻断这些细胞的功能，以了解它们在可卡因和/或逆转录病毒暴露引起的缺血和心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效应。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的病因的理解。我们将通过我们成熟的方法来限制逆转录病毒感染和酒精暴露对心脏的有害影响，这些方法可以防止大部分细胞因子失调和心脏氧化损伤：T细胞受体Vbeta8.1、多种抗氧化剂和维生素E补充剂。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和酒精暴露的小鼠的心脏毒性。这类研究可能为它们应用于减少酗酒、艾滋病毒感染患者的心脏病提供基础。