RELATIONSHIP OF CYTOKINES TO ALCOHOLIC LIVER DISEASE

细胞因子与酒精性肝病的关系

• 批准号: 3801933
• 负责人: R L VEECH
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3801933
• 关键词: HIV infections; MHC class II antigen; acetates; alcoholic hepatitis; alcoholic liver cirrhosis; alcoholism /alcohol abuse; biomarker; blood chemistry; cytokine; drug withdrawal; human subject; interferons; interleukin 1; liver function; longitudinal human study; transforming growth factors; tumor necrosis factor alpha

The purpose of this study was to determine the role which chronic exposure to ethanol and its metabolic product acetate play in altering the function of the immune system in alcoholics and subjects with alcoholic hepatitis and alcoholic cirrhosis. Earlier we had shown that elevation of plasma tumor necrosis factor ` (TNF `) predicted death in patients with severe alcoholic hepatitis. Elevation of no other acute Phase cytokine was found to do so, nor was there a correlation with standard liver function tests, nor with abstinence after discharge from 30 days in hospital. In order to further examine alterations in immune function in alcoholics we determined this year, that plasma levels of interferon gamma(IFNgamma) were elevated in alcoholic subjects without clinically obvious liver disease during withdrawal from alcohol. Correlated with this elevation of IFNgamma, there was the expected increase in the expression of MHC class I antigens circulating mononuclear cells, but a paradoxical decrease in expression of MHC class II protein on the cell surface of circulating leukocytes. Finally, it was determined that end stage renal disease patients, exposed to 1.5 mM acetate but without exposure to ethanol as a precursor showed acute elevation within 4 hours of circulating transforming growth factor ~ (TGF~) during hemodialysis. TGF~ is associated with the production of fibrosis and collagen formation, a prominent feature of alcoholic cirrhosis, while TNFalpha is associated with cell death, also a prominent feature of alcoholic cirrhosis and alcoholic hepatitis. This finding of widespread abnormalities in alcoholics begin to present a coherent pattern of alteration in immune function by ethanol and its metabolite acetate which may have clinical significance not only for our understanding of pathogenesis, but also for improved treatment of the severe and often fatal medical consequences of alcoholism. These findings also have implications for HIV-1 infection and progression of disease in a group of poly drug abusers, who also abuse alcohol, and constitute a high risk group for HIV-1 infection.

本研究的目的是确定慢性病的作用 接触乙醇及其代谢产物乙酸盐会改变 酗酒者和患有此病的受试者的免疫系统功能 酒精性肝炎和酒精性肝硬化。 早些时候我们已经证明了 血浆肿瘤坏死因子`（TNF`）的升高预测死亡 严重酒精性肝炎患者。 无其他急性升高 发现相细胞因子有这种作用，并且与 标准肝功能检查，出院后也没有禁欲 住院30天。 为了进一步检测免疫变化 我们今年确定了酗酒者的功能，血浆水平 酗酒者的干扰素γ（IFNgamma）升高，但没有 戒酒期间出现临床明显的肝脏疾病。 与 IFNgamma 的升高相关，预期 循环中 MHC I 类抗原表达增加 单核细胞，但 MHC 类表达却相反下降 循环白细胞细胞表面的 II 蛋白。 最后，是 确定终末期肾病患者暴露于 1.5 mM 醋酸盐但没有暴露于乙醇作为前体，表现出急性 循环转化生长因子4小时内升高~ (TGF~) 血液透析期间。 TGF~ 与以下物质的产生有关 纤维化和胶原蛋白形成，酒精的一个显着特征 肝硬化，而 TNFα 与细胞死亡相关，也是一个重要的 酒精性肝硬化和酒精性肝炎的特点。 这一发现 酗酒者中普遍存在的异常开始呈现出连贯的 乙醇及其代谢物改变免疫功能的模式 醋酸盐可能不仅对我们有临床意义 了解发病机制，也有利于改善治疗 酗酒造成严重且往往致命的医疗后果。 这些 研究结果对 HIV-1 感染和疾病进展也有影响 一群同时滥用药物和酗酒的人患有疾病，以及 构成HIV-1感染的高危人群。