INTERLEUKIN 6 ROLE IN ALCOHOLIC LIVER CIRRHOSIS

白细胞介素 6 在酒精性肝硬化中的作用

基本信息

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
项目类别：
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

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

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项目摘要

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.

肝肝硬化是全球死亡的主要原因之一。可归因于肝肝硬化的死亡中约有50％识别酒精为主要的候选剂。目前，没有接受治疗这种疾病。可用的治疗主要针对肝硬化并不抑制炎症或纤维化机制。花费了近30亿美元 1992年治疗肝肝硬化患者。开发这种疾病的治疗将减轻数十万，将为美国政府节省数百万美元美元。酒精性肝炎患者有几个急性相反应的表现（APR）。他们也有升高 IL-1，IL-6和TNF-alpha的水平。这些相同的细胞因子参与细胞损伤和通过肝脂肪的细胞外基质产生细胞。我们获得了证据表明IL-6是纤维纤维诱导α1（i）胶原mRNA的表达的细胞因子。在此外，TNF-α是一种介导细胞损伤的细胞因子。所以，抑制细胞因子的合成和/或分泌的药物或阻止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。但是，其作用机理尚待阐明。最近的证据表明秋水仙碱抑制了细胞因子的释放和生长因子，可防止TNF-Alpha和增强TNF-α溶解受体的释放。长期该建议的目标是评估APR的贡献，以及IL-1，IL-6和TNF-α在肝肝硬化和探索秋水仙碱的抗炎和抗纤维化潜力。我们的具体目的是：（1）调查APR的机制有助于肝纤维化并确定通过哪种细胞因子调节脂肪存储中I型胶原基因的表达细胞。秋水仙碱阻止APR的机制将是探索。（2）研究IL-1，IL-6和TNF-α在诱导中的作用酒精性肝硬化的大鼠模型中的过量基质沉积和评估秋水仙碱作为治疗剂的有效性酒精性肝肝硬化。如果我们能更好地理解机制秋水仙碱可防止肝纤维化并改善肝功能可以测试许多人的抗炎和抗纤维化潜力化合物，包括当前大量的秋水仙碱衍生物可用的。