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: 6437092
• 负责人: RONALD Ross WATSON
• 金额: $ 1.53万
• 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/6437092
• 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.

心肌病和左心室功能障碍在艾滋病患者或长期饮酒者中很常见。 然而，几乎没有人知道逆转录病毒感染和酒精对心脏病的综合影响。 我们的鼠逆转录病毒感染模拟了在HIV感染期间发现的许多细胞因子失调，提示心脏毒性的炎症损伤。 我们发现，酒精消费加剧了许多免疫，氧化和营养缺陷，由于鼠逆转录病毒感染。 我们发现，酒精+逆转录病毒暴露是特别有毒的，增加Th 2和减少Th 1细胞因子，显着降低心脏维生素E，增加心脏脂质的氧化和协同促进严重的心脏损伤由于科萨基B3感染。 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。 这些作用应促进心肌营养病原体的生长和发病机制。 将在逆转录病毒和/或乙醇暴露期间使用小鼠的科萨基B感染来研究该假设。将使用室间导管在体内定量左心室功能，以定义心室功能障碍并表征酒精的影响。 我们将确定酒精和/或逆转录病毒暴露诱导的炎症反应对心肌缺血事件和梗死的贡献。 我们将断言免疫机制涉及中性粒细胞在放大缺血性损伤可卡因加逆转录病毒暴露。 我们将评估白细胞粘附和定位，血小板-白细胞相互作用，并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。 我们将断言逆转录病毒感染前后酒精暴露的心脏毒性作用。 我们的模型研究将增加对心脏病理学中酒精+逆转录病毒诱导的免疫功能障碍的病因学的理解。 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，我们已经证明的方法可以防止大部分细胞因子失调和对心脏的氧化损伤：T细胞受体Vbeta 8.1，多种抗氧化剂和维生素E补充剂。 我们假设，我们的治疗将限制逆转录病毒感染，酒精暴露小鼠的细胞因子失调，从而心脏毒性。这些研究可以为他们的应用提供基础，以减少酗酒，艾滋病毒感染患者的心脏病。