INTERLEUKIN 6 ROLE IN ALCOHOLIC LIVER CIRRHOSIS

肝硬变是世界范围内主要的死亡原因之一。 大约50%的可归因于肝硬变的死亡承认 酒精是主要的人种学因素。目前，还没有接受的 治疗这种疾病的方法。可用的治疗主要是针对 对肝硬变的并发症，而不是抑制炎症或 导致纤维化的机制。近30亿美元被花费在 1992年对肝硬变患者的治疗。因此， 这种疾病的治疗方法的开发将减轻……的痛苦 数十万美元，将为美国政府节省数百万美元 美元。酒精性肝炎患者有几种 急性时相反应(APR)的表现。他们还提升了 IL-1、IL-6和肿瘤坏死因子-α水平。这些相同的细胞因子参与了 肝脏脂肪储存对细胞的损伤和细胞外基质的产生 细胞。我们已经获得的证据表明，IL-6是一种纤维化 诱导α1(I)前胶原基因表达的细胞因子。在……里面 此外，肿瘤坏死因子-α是一种介导细胞损伤的细胞因子。因此， 抑制细胞因子合成和/或分泌的药物或阻止 其生物活性可改善肝硬变。秋水仙碱是 一种孤儿药物，已被成功地用于治疗 肝硬变。但其作用机制尚不清楚。 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，防止肿瘤坏死因子-α的细胞毒作用和 促进肿瘤坏死因子-α可溶性受体的释放。长期的 这项提案的目标是评估《亚太报告》的贡献， 白介素1、白介素6和肿瘤坏死因子-α在肝硬变和肝纤维化发展中的作用 探索秋水仙碱的抗炎和抗纤维化作用。 我们的具体目标是：(1)研究APR 有助于肝纤维化，并通过以下方式确定其分子机制 哪些细胞因子在脂肪储存中调节I型胶原基因的表达 细胞。秋水仙碱预防APR的机制将是 探索过了。(2)研究IL-1、IL-6和肿瘤坏死因子-α在诱导 酒精性肝硬变大鼠模型中过度的基质沉积，以及 秋水仙碱治疗慢性粒细胞白血病的疗效评价 酒精性肝硬变。如果我们能更好地理解 秋水仙碱通过哪些途径预防肝纤维化和改善肝功能 可以测试许多抗炎和抗纤维化的潜力 化合物，包括目前大量的秋水仙素衍生物 可用。

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.