INTERLEUKIN 6 ROLE IN ALCOHOLIC LIVER CIRRHOSIS

肝硬化是世界范围内死亡的主要原因之一。 大约50%的死于肝硬化的人认识到， 酒精是主要的精神因素。 目前，没有接受 治疗这种疾病。 现有的治疗方法主要针对 肝硬化的并发症，而不是抑制炎症或 纤维化机制 近30亿美元用于 1992年治疗肝硬化患者。 因此 开发治疗这种疾病的方法将减轻 数十万，将节省美国政府数百万美元， 美元. 酒精性肝炎患者有几种 急性期反应（APR）。 他们还提高了 IL-1、IL-6和TNF-α水平。 这些细胞因子参与了 肝贮脂对细胞损伤及细胞外基质的产生 细胞 我们已经获得的证据表明IL-6是一种纤维化因子， 诱导α 1（I）前胶原mRNA表达的细胞因子。 在 此外，TNF-α是介导细胞损伤的细胞因子。 因此，我们认为， 抑制细胞因子的合成和/或分泌或预防 其生物活性可改善肝硬化。 秋水仙碱是 一种孤儿药，已成功用于治疗 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 该提案的目的是评估APR的贡献， 以及IL-1、IL-6和TNF-α在肝硬化发展中的作用， 探讨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，并确定分子机制， 哪些细胞因子调节I型胶原基因在脂肪储存中的表达 细胞 秋水仙碱预防APR的机制将是 探讨了 (2)研究IL-1、IL-6和TNF-α在诱导人肝癌细胞凋亡中的作用， 在酒精性肝硬化大鼠模型中过量基质沉积，和 评估秋水仙碱作为治疗药物的有效性， 酒精性肝硬化 如果我们能更好地理解 秋水仙碱通过预防肝纤维化和改善肝功能， 可以测试抗炎和抗纤维化的潜力， 化合物，包括目前大量的秋水仙碱衍生物， available.

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.