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: 6537702
• 负责人: RONALD Ross WATSON
• 金额: $ 41.66万
• 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/6537702
• 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酗酒的人中很常见。 然而，关于逆转录病毒感染和酒精对心脏病的综合影响几乎一无所知。 我们的小鼠逆转录病毒感染模仿了艾滋病毒感染期间发现的许多细胞因子失调，从而导致心脏毒性的炎症损伤。 我们发现，饮酒会加剧由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+逆转录病毒暴露毒性特别大，会增加 Th2 细胞因子并减少 Th1 细胞因子，显着降低心脏维生素 E，增加心脏脂质氧化，并协同促进柯萨奇 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会诱发免疫功能障碍和氧化，从而增加心血管疾病的发生。 这些作用应该促进心肌营养病原体的生长和发病机制。 该假设将通过逆转录病毒和/或乙醇暴露期间小鼠的柯萨奇 B 感染进行研究。将通过心室间导管对左心室功能进行体内定量，以确定心室功能障碍并表征酒精的影响。 我们将确定酒精和/或逆转录病毒暴露引起的炎症反应对心肌缺血事件和梗塞的影响。 我们将断言涉及中性粒细胞的免疫机制在可卡因加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，并用药物阻断这些细胞的功能，以了解它们在可卡因和/或逆转录病毒暴露引起的缺血和心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对心脏的毒性作用。 我们的模型研究将增加对心脏病理学中酒精+逆转录病毒引起的免疫功能障碍的病因学的了解。 我们将通过我们行之有效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。这些研究可以为其应用提供基础，以减少酗酒、艾滋病毒感染者的心脏病。