RELATIONSHIP OF CYTOKINES TO ALCOHOLIC LIVER DISEASE

细胞因子与酒精性肝病的关系

• 批准号: 3789493
• 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/3789493
• 关键词: MHC class I antigen; MHC class II antigen; acetates; alcoholic hepatitis; alcoholic liver cirrhosis; alcoholism /alcohol abuse; biomarker; chronic renal failure; drug withdrawal; ethanol; gene expression; hemodialysis; immunogenetics; immunoregulation; immunotoxicity; interferons; monocyte; transforming growth factors; tumor necrosis factor alpha

The purpose of thsi study was to determine the role which chronic exposure to ethanol and its metabolic product acetate play in altering some paremeters of the immune system in alcoholics and subjects with alcoholic hepatitis amd alcohlic cirrhosis. Earlier we had shown that elevation of plasma tumor necrosis factor alpha (TNF alpha) 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. TNF alpha is secreted by monocytic-phagocitic cells and cytotoxic T lymphocytes. In order to further examine alterations in immune function in alcoholics we determined that plasma levels of interferon gamma (IFN gamma) were elevated inalcoholic subjects without clinically obvious liver disease during withdrawal from alcoholic dependence. Correlated with this elevation of IFN gamma, there was an expected increase in the expression of major histocompatibility complex (MHC) class I antigens, but a paradoxical decrease in expression of MHC class II protein on circulating mononuclear cells. 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 beta (TGFbeta) during hemodialysis. TGFbeta 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 immue function by ethanol and its metabolite acetate which may have clinical significance not only for our understanding of pathogenesis, but also for improved treatment if the severe and ofter fatal medical consequences of alcoholism. These findings also have implications for HIV-1 infection and progression of disease in a group of poly abusers, who also use alcohol, and constitute a high risk group for HIV-1 infection.

这项研究的目的是确定长期暴露的作用 乙醇及其代谢产物乙酸盐在改变一些 酗酒者和酗酒者的免疫系统参数 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α（TNFα）预测患者死亡 患有严重的酒精性肝炎。 无其他急性期升高 发现细胞因子有这种作用，并且与标准也没有相关性 肝功能检查，出院后30天也没有禁欲 医院。 TNFα由单核吞噬细胞分泌， 细胞毒性T淋巴细胞。 为了进一步检验变化 酗酒者的免疫功能我们确定血浆水平 酒精中的干扰素γ（IFNγ）升高，但没有 戒酒期间出现临床明显的肝病 依赖性。 与 IFN γ 升高相关的是 主要组织相容性复合体表达的预期增加 (MHC) I 类抗原，但 MHC 表达却相反下降 循环单核细胞上的 II 类蛋白。 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β 4 小时内升高 （TGFbeta）在血液透析期间。 TGFbeta 与生产有关 纤维化和胶原蛋白形成，这是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 酗酒者普遍存在的异常开始呈现出连贯的模式 乙醇及其代谢产物乙酸盐改变免疫功能的研究 这不仅对我们理解具有临床意义 发病机制，而且如果病情严重且经常发生，也可用于改善治疗 酗酒造成致命的医疗后果。 这些发现也有 对一组人群中 HIV-1 感染和疾病进展的影响 聚滥用者，他们也使用酒精，并且构成了高风险群体 HIV-1 感染。