BASES OF CIRRHOSIS IN ALCOHOLIC LIVER DISEASE

这项提议是对我们最初的 目的：试图了解其分子机制 对肝纤维化负有责任。最终的共同之路 它发生在各种形式的肝纤维化中，无论其病因如何 是细胞外基质沉积增多。我们假设 这个过程，包括细胞损伤，招募和 炎性细胞和间充质细胞的增殖以及 细胞外基质的合成和降解，是由 包括细胞因子在内的各种可溶性多肽。该计划的目标是 目前的提议是定义这些调节器的作用 细胞因子在肝纤维化中的作用及其机制 这些效应器蛋白可以被调控。具体目标：1. 为了描述细胞因子在时间上的表达， 酒精性肝病的发病机制。2.确定哪一项 酒精性肝病的细胞类型正在合成细胞因子。 3.探讨乙醇对细胞因子基因表达的影响。4. 前列腺素E2(PGE2)对基质的影响 沉积、细胞因子合成与转化生长因子-β (转化生长因子-β)受体。5.调查抑制的效果 我们的酒精性肝病大鼠模型的细胞因子活性。 方法：致纤维化细胞因子对细胞外液的影响 基质蛋白质的合成和沉积将在小学阶段学习。 培养肝细胞、Ito细胞和Kupffer细胞，并在 酒精性肝纤维化大鼠灌胃模型的建立。 细胞因子和细胞外基质的合成将通过 Northern杂交分析，核连续分析， 形态分析、生化测定和放射免疫分析。在……里面 将使用原位杂交分析来定位细胞因子 在酒精性肝病动物模型和人类肝脏中 标本。前列腺素E_2作为一种抗纤维化药物的意义 在相同的体内和体外模型系统中进行评估，而 其对转化生长因子-β受体的影响将通过亲和力来研究。 交叉链接研究。转化生长因子-β和白介素I的活性将 特异性受体在体内模型中的抑制作用 对抗者。与健康相关：通过实现这一目标 建议我们将制定一个一般的发病机制模型。 酒精性肝病，从而有助于制定 理性治疗。

This proposal represents a continuation and expansion of our initial objective of attempting to understand the molecular mechanisms responsible for hepatic fibrogenesis. The final common pathway which occurs in all forms of liver fibrosis regardless of etiology is the increased deposition of extracellular matrix. We hypothesize that this process, which includes cell damage, recruitment and proliferation of inflammatory and mesenchymal cells, as well as extracellular matrix synthesis and degradation, is orchestrated by a variety of soluble peptides including cytokines. The aims of the present proposal are to define the role of these modulatory cytokines in hepatic fibrosis and to investigate the mechanisms by which these effector proteins can be regulated. Specific Aims: 1. To delineate the temporal expression of the cytokines involved in the pathogenesis of alcoholic liver disease. 2. To determine which cell types are synthesizing cytokines in alcoholic liver disease. 3. To ascertain how ethanol influences cytokine gene expression. 4. To determine the effects of prostaglandin E2 (PGE2) on matrix deposition, cytokine synthesis and transforming growth factor-beta (TGF-beta)receptors. 5. To investigate the effects of inhibiting cytokine activity in our rat model of alcoholic liver disease. Methods: The effects of the fibrogenic cytokines on extracellular matrix protein synthesis and deposition will be studied in primary cultures of hepatocytes, Ito cells, and Kupffer cells, and in the rat intragastric feeding model of alcohol-induced liver fibrosis. Cytokine and extracellular matrix synthesis will be evaluated by Northern hybridization analysis, nuclear run-on assays, morphological analysis, biochemical determinations, and RIAs. In situ hybridization analysis will be employed to localize cytokines in the animal model of alcoholic liver disease and in human liver specimens. The significance of PGE2 as an antifibrogenic agent will be evaluated in the same in vivo and in vitro model systems, while its effects on TGF-beta receptors will be investigated by affinity cross-linking studies. TGF-beta and interleukin-I activity will be inhibited in the in vivo model by the use of specific receptor antagonists. Health Relatedness: By accomplishing the aims of this proposal we shall formulate a general model for the pathogenesis of alcoholic liver disease and thereby aid in the formulation of rational therapy.