ALCOHOL, NUTRITION, AND IMMUNOMODULATION

酒精、营养和免疫调节

• 批准号: 2667592
• 负责人: CRAIG J. MCCLAIN
• 金额: $ 28.31万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2667592
• 关键词: AIDS; HIV infections; Kupffer's cell; S adenosylmethionine; alcoholic hepatitis; alcoholic liver cirrhosis; antioxidants; cellular pathology; clinical research; disease /disorder model; ethanol; free radical oxygen; glutathione; human subject; human therapy evaluation; interleukin 8; laboratory mouse; laboratory rat; liver disorder chemotherapy; mitochondria; nuclear factor kappa beta; oxidative stress; superoxide dismutase; tocopherols; tumor necrosis factor alpha

Tumor necrosis factor (TNF) is a macrophage/monocyte-derived inflammatory cytokine whose dysregulation has been shown by us and others to play an important role in the pathophysiology of several forms of liver injury including that observed in alcoholic liver disease (ALD). TNF also has been postulated to play a pivotal role in the metabolic complications and wasting of Acquired Immunodeficiency Syndrome (AIDS). There are great similarities between the metabolic abnormalities/complications of AIDS and ALD including anorexia, cachexia, immune suppression, hypoalbuminemia, increased acute phase reactants and edema, to name only a few. We have demonstrated increased plasma TNF, increased monocyte TNF production, and increased hepatic immunohistochemical staining for TNF in patients with ALD. Mitochondrial dysfunction/structural damage is an early event in ALD, and it has also been postulated to play a role in organ dysfunction in AIDS. TNF, per se, causes mitochondrial dysfunction/damage including inhibition of respiration, superoxide generation, and ultimately cell injury. Impairment of normal mitochondrial respiration markedly enhances TNF cytotoxicity. TNF mediated cytotoxicity is thought to be an oxidant injury, and TNF induction of the mitochondrial antioxidant manganous superoxide dismutase (MnSOD) is an endogenous protective mechanism to prevent ongoing TNF cytotoxicity. Regulation of cytokines such as TNF has become a focal point for therapeutic intervention in many diseases including ALD and AIDS. NFkappaB is a transcription factor for several cytokines including TNF and for the HIV virus. NFkappaB is activated by reactive oxygen intermediates, and this activation can be blocked by antioxidants such as vitamin E (Vit E) and glutathione (GSH)-enhancing agents in certain transformed cell lines. It is our working hypothesis that TNF plays an etiologic role in many of the clinical/biochemical abnormalities observed in ALD and AIDS. We postulate that chronic alcohol abuse and HIV infection cause increased gut permeability and endotoxemia, depletion of many nutrient antioxidants (e.g., GSH, Vit E), generation of reactive oxygen intermediates, activation of NFkappaB, increased TNF production, mitochondrial dysfunction with mitochondrial GSH depletion, and ultimately wasting and organ dysfunction including liver injury. The overall research goals of this laboratory are to further define mechanisms and modulatory pathways whereby cytokines, such as TNF, induce metabolic disturbances/liver injury in ALD and in AIDS, with the ultimate goal being development of specific "anticytokine" therapy for ALD and for AIDS. The specific objectives in this proposal (initially performed in ALD patients) are to: 1) Evaluate dysregulated cytokine (TNF, IL-8) production in ALD, the role of antioxidant status and NFkappaB activation in modulating this cytokine production and the role of "anticytokine" therapy; 2) Determine the role of mitochondrial dysfunction/protection in alcohol/TNF-mediated hepatotoxicity; and 3) Determine whether unique forms of antioxidant therapy attenuate dysregulated TNF production and mitochondrial dysfunction in patients with ALD. This research spans the spectrum from molecular cellular studies to applied human investigations, with the ultimate goal being improved knowledge and therapy for these two devastating disease processes with overlapping metabolic complications.

肿瘤坏死因子（TNF）是巨噬细胞/单核细胞衍生的炎症 Cytokine的失调已被我们和其他人表现出来 在几种形式的肝损伤的病理生理学中的重要作用 包括在酒精性肝病（ALD）中观察到的。 TNF也有 假设在代谢并发症中起关键作用 浪费获得的免疫缺陷综合征（AIDS）。 有很多 艾滋病的代谢异常/并发症与并发症与 ALD包括厌食症，恶病质，免疫抑制，低珠蛋白酶血症， 增加了急性相应物和水肿，仅举几例。 我们有 证明血浆TNF增加，单核细胞TNF产生增加，并且 TNF患者的TNF肝免疫组织化学染色增加 阿尔德。 线粒体功能障碍/结构性损害是早期事件 ALD，也已经假设它在器官功能障碍中发挥作用 在艾滋病中。 本身TNF会引起线粒体功能障碍/损害 抑制呼吸，超氧化物产生和最终细胞 受伤。 正常线粒体呼吸的损害显着增强 TNF细胞毒性。 TNF介导的细胞毒性被认为是氧化剂 线粒体抗氧化剂的损伤和TNF诱导 超氧化物歧化酶（MNSOD）是一种内源性保护机制 防止持续的TNF细胞毒性。 调节TNF等细胞因子的调节 成为许多疾病治疗干预的焦点 包括ALD和AIDS。 nfkappab是多个的转录因子 包括TNF和HIV病毒在内的细胞因子。 nfkappab被激活 活性氧中间体，这种激活可以被阻止 抗氧化剂，例如维生素E（VIT E）和谷胱甘肽（GSH）增强物 某些转化的细胞系中的代理。 这是我们的工作假设 TNF在许多临床/生化中起病因的作用 在ALD和AIDS中观察到异常。 我们假设慢性酒精 滥用和艾滋病毒感染会增加肠道渗透性和内毒素血症， 许多营养抗氧化剂的耗竭（例如GSH，VIT E），生成 活性氧中间体，NFKappab的激活，增加了TNF 生产，线粒体功能障碍，线粒体GSH耗竭， 最终浪费和器官功能障碍，包括肝损伤。 这 该实验室的总体研究目标是进一步定义机制 和调节途径，诸如TNF之类的细胞因子诱导代谢 ALD和AIDS中的干扰/肝损伤，最终目标是 开发针对ALD和AIDS的特定“抗细菌”疗法。 这 该提案中的特定目标（最初在ALD患者中执行） 为：1）评估ALD中的细胞因子（TNF，IL-8）的失调， 抗氧化剂状态和NFKappab激活在调节此的作用 细胞因子产生和“抗细菌”疗法的作用； 2）确定 线粒体功能障碍/保护在酒精/TNF介导的作用 肝毒性； 3）确定是否独特的抗氧化剂形式 治疗减弱了TNF产生和线粒体失调 ALD患者的功能障碍。 这项研究跨越了 分子细胞研究用于应用人类研究， 最终目标是改善这两个的知识和治疗 毁灭性的疾病过程，与代谢并发症重叠。