INTERLEUKIN 6 ROLE IN ALCOHOLIC LIVER CIRRHOSIS

白细胞介素 6 在酒精性肝硬化中的作用

• 批准号: 2389919
• 负责人: MARCOS ROJKIND
• 金额: $ 18.91万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2389919
• 关键词: acute phase protein; adipocytes; alcoholic liver cirrhosis; antifibrinolytic agents; antiinflammatory agents; colchicine; collagen; collagenase; cytokine; cytokine receptors; disease /disorder model; extracellular matrix; fibrogenesis; fibrosis; gene expression; inflammation; interleukin 1; interleukin 6; laboratory rat; liver cells; liver pharmacology; northern blottings; tissue /cell culture; tissue inhibitor of metalloproteinases; tumor necrosis factor alpha

Liver cirrhosis is among the leading causes of death worldwide. Approximately 50% of the deaths attributable to liver cirrhosis recognize alcohol as the main ethiologic agent. Currently, there is no accepted treatment for this disease. The available treatment is directed primarily to complications of cirrhosis and not to inhibit the inflammatory or fibrogenic mechanisms. Close to 3 billion dollars were spent for the treatment of patients with liver cirrhosis in 1992. Therefore, the development of a treatment for this disease will relieve the suffering of hundreds of thousands and will save the USA government millions of dollars. Patients with alcoholic hepatitis have several of the manifestations of the acute-phase response (APR). They also have elevated levels of IL-1, IL-6 and TNF-alpha. These same cytokines are involved in cell injury and production of extracellular matrix by liver fat-storing cells. We have obtained evidence to suggest that IL-6 is a fibrogenic cytokine that induces the expression of alpha1(I) procollagen mRNA. In addition, TNF-alpha is a cytokine that mediates cell injury. Therefore, drugs that inhibit synthesis and/or secretion of cytokines or that prevent their biological activity could ameliorate liver cirrhosis. Colchicine is an orphan drug that has been used successfully for the treatment of cirrhosis. However, its mechanism of action remains to be elucidated. Recent evidence suggests that colchicine inhibits the release of cytokines and growth factors, prevents the cytotoxic effect of TNF-alpha and enhances the release of TNF-alpha soluble receptors. The long-term objectives of this proposal are to evaluate the contribution of the APR, and of IL-1, IL-6 and TNF-alpha in the development of liver cirrhosis and explore the anti-inflammatory and anti-fibrogenic potential of colchicine. Our specific aims are: (1) To investigate the mechanisms by which the APR contributes to liver fibrosis and to determine the molecular mechanisms by which cytokines modulate type I collagen gene expression in fat-storing cells. The mechanisms by which colchicine prevents the APR will be explored. (2) To study the role of IL-1, IL-6 and TNF-alpha in inducing excess matrix deposition in a rat model of alcoholic cirrhosis, and evaluate the effectiveness of colchicine as a therapeutic agent for alcoholic liver cirrhosis. If we could better understand the mechanisms by which colchicine prevents liver fibrosis and improves liver function we could test the anti-inflammatory and anti-fibrogenic potential of many compounds, including a large number of colchicine derivatives currently available.

肝硬化是全世界导致死亡的主要原因之一。 大约 50% 的死亡归因于肝硬化 酒精为主要致病因素。 目前，还没有接受 治疗这种疾病。 可用的治疗主要针对 肝硬化并发症而不是抑制炎症或 纤维化机制。 花费了近30亿美元 1992年开始治疗肝硬化患者。因此， 开发这种疾病的治疗方法将减轻患者的痛苦 数十万，将为美国政府节省数百万美元 美元。 酒精性肝炎患者有以下几种症状 急性期反应（APR）的表现。 他们也有升高的 IL-1、IL-6 和 TNF-α 水平。 这些相同的细胞因子参与 肝脏脂肪储存造成的细胞损伤和细胞外基质的产生 细胞。 我们已经获得证据表明 IL-6 是一种纤维形成物质 诱导 α1(I) 前胶原 mRNA 表达的细胞因子。 在 此外，TNF-α是一种介导细胞损伤的细胞因子。 所以， 抑制细胞因子合成和/或分泌或阻止细胞因子合成和/或分泌的药物 它们的生物活性可以改善肝硬化。 秋水仙碱是 已成功用于治疗的孤儿药 肝硬化。 然而，其作用机制仍有待阐明。 最近的证据表明秋水仙碱抑制细胞因子的释放 和生长因子，防止 TNF-α 的细胞毒性作用 增强 TNF-α 可溶性受体的释放。 长期来看 该提案的目标是评估 APR 的贡献， 以及IL-1、IL-6和TNF-α在肝硬化发展中的作用 探索秋水仙碱的抗炎和抗纤维化潜力。 我们的具体目标是：（1）研究APR的机制 有助于肝纤维化并通过以下方式确定其分子机制 哪些细胞因子调节脂肪储存中的 I 型胶原蛋白基因表达 细胞。 秋水仙碱预防 APR 的机制是 探索过。 (2)研究IL-1、IL-6和TNF-α在诱导中的作用 酒精性肝硬化大鼠模型中的过量基质沉积，以及 评估秋水仙碱作为治疗剂的有效性 酒精性肝硬化。 如果我们能更好地理解其中的机制 秋水仙碱可以预防肝纤维化并改善肝功能 可以测试许多物质的抗炎和抗纤维化潜力 化合物，包括目前大量的秋水仙碱衍生物 可用的。