ALCOHOL, NUTRITION, AND IMMUNOMODULATION

酒精、营养和免疫调节

• 批准号: 6430831
• 负责人: CRAIG J. MCCLAIN
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6430831
• 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.

肿瘤坏死因子是一种巨噬细胞/单核细胞来源的炎症。 细胞因子，其失调已被我们和其他人证明扮演着一种 几种形式的肝损伤在病理生理中的重要作用 包括在酒精性肝病(ALD)中观察到的。肿瘤坏死因子也有 被认为在代谢并发症和 消磨获得性免疫缺陷综合症(艾滋病)。有很多很棒的 艾滋病的代谢异常/并发症与 ALD包括厌食症、恶病质、免疫抑制、低蛋白血症、 急性期反应物增加和浮肿，仅举几例。我们有 表现为血浆肿瘤坏死因子升高，单核细胞肿瘤坏死因子产生增加，以及 慢性肝炎患者肝脏肿瘤坏死因子免疫组化染色增强 ALD.线粒体功能障碍/结构损伤是一种早期事件 ALD，它也被认为在器官功能障碍中发挥作用 在艾滋病方面。肿瘤坏死因子本身会导致线粒体功能障碍/损伤，包括 抑制呼吸、超氧化物生成，并最终抑制细胞 受伤。正常线粒体呼吸的损害显著增强 肿瘤坏死因子细胞毒作用。肿瘤坏死因子介导的细胞毒性被认为是一种氧化剂 线粒体抗氧化剂锰的损伤及肿瘤坏死因子的诱导 超氧化物歧化酶(MnSOD)是一种内源性保护机制 防止持续的肿瘤坏死因子细胞毒性。对肿瘤坏死因子等细胞因子的调节 成为许多疾病治疗干预的焦点 包括ALD和艾滋病。NFkappaB是一种转录因子 包括肿瘤坏死因子和艾滋病毒在内的细胞因子。NFkappaB通过以下方式激活 活性氧中间体，这种激活可以被阻断 抗氧化剂，如维生素E(维生素E)和谷胱甘肽(GSH)-增强 某些转化细胞系中的药物。这是我们的工作假设 肿瘤坏死因子在许多临床/生化疾病中起病因学作用 在ALD和AIDS中观察到的异常。我们假设长期饮酒 滥用和艾滋病毒感染会导致肠道通透性增加和内毒素血症， 许多营养抗氧化剂(如谷胱甘肽、维生素E)的消耗，产生 活性氧中间体，激活NFkappaB，增加肿瘤坏死因子 生产，线粒体功能障碍和线粒体谷胱甘肽耗竭， 最终导致消瘦和器官功能障碍，包括肝脏损伤。这个 这个实验室的总体研究目标是进一步定义机制 以及细胞因子，如肿瘤坏死因子，诱导代谢的调节途径 ALD和AIDS的紊乱/肝损伤，最终目标是 阿尔茨海默病和艾滋病特异性“抗细胞因子”疗法的发展。这个 本方案中的具体目标(最初在ALD患者中执行) 目的：1)评价ALD患者细胞因子(肿瘤坏死因子、白介素8)的异常产生； 抗氧化状态和NFkappaB激活在调节这一过程中的作用 细胞因子的产生和“抗细胞因子”治疗的作用；2)测定 线粒体功能障碍/保护在酒精/肿瘤坏死因子介导中的作用 肝脏毒性；以及3)确定独特形式的抗氧化剂 治疗减轻失调的肿瘤坏死因子的产生和线粒体 酒精性肝病患者的功能障碍。这项研究的范围从 分子细胞研究应用于人类研究，与 最终目标是提高这两个人的知识和治疗水平 具有重叠代谢并发症的破坏性疾病过程。

项目成果

Hyperhyaluronanemia in alcoholic hepatitis is associated with increased levels of circulating soluble intercellular adhesion molecule-1.

• DOI: 10.1111/j.1530-0277.1998.tb03915.x
• 发表时间: 1998-09
• 期刊: Alcoholism, clinical and experimental research
• 作者: D. Hill;I. Deaciuc;C. McClain

Mechanisms of alcohol-mediated CD4+ T lymphocyte death: relevance to HIV and HCV pathogenesis.

酒精介导的 CD4 T 淋巴细胞死亡机制：与 HIV 和 HCV 发病机制的相关性。

• DOI: 10.2741/a872
• 发表时间: 2002
• 期刊: Frontiers in bioscience : a journal and virtual library.
• 作者: Barve,ShirishS;Kelkar,SujataV;Gobejishvilli,Leila;Joshi-Barve,Swati;McClain,CraigJ
• 通讯作者: McClain,CraigJ

Mechanisms and cell signaling in alcoholic liver disease.

• DOI: 10.1515/bc.2010.137
• 发表时间: 2010-11
• 期刊: Biological chemistry
• 影响因子: 3.7
• 作者: Beier JI;McClain CJ
• 通讯作者: McClain CJ

Ethanol enhances activation-induced caspase-3 dependent cell death in T lymphocytes.

乙醇可增强 T 淋巴细胞中激活诱导的 caspase-3 依赖性细胞死亡。

• 发表时间: 2002
• 期刊: Alcoholism, clinical and experimental research.
• 作者: Kelkar,Sujata;Dong,Qing;Xiao,Yinghua;Joshi-Barve,Swati;McClain,CraigJ;Barve,ShirishS
• 通讯作者: Barve,ShirishS

Role of Zinc in the Development/Progression of Alcoholic Liver Disease.

• DOI: 10.1007/s11938-017-0132-4
• 发表时间: 2017-06
• 期刊: Current treatment options in gastroenterology
• 作者: McClain C;Vatsalya V;Cave M
• 通讯作者: Cave M