PATHOGENESIS OF EXPERIMENTAL ALCOHOLIC LIVER DISEASE

目的：探讨酒精性肝病的发病机制， 饮食干预和预防性药物将有可能 减少这种疾病。 具体目的：生产酒精性肝病， 人ALD包括脂肪改变、炎症、坏死和纤维化， 连续灌胃给予规定饮食和酒精的大鼠的肝脏 喂食 这种饮食养生法是以一种方式修改， 一种饮食成分，即脂肪，当大鼠被 进料乙醇。 产生ALD的饮食含有25%的卡路里， 玉米油。 预防ALD的饮食替代玉米油， 脂肪（25%的卡路里）。 使用这两种饮食疗法， 产生ALD和不产生ALD的大鼠将被分析 存在生化和形态学异常，以确定 哪些异常与酒精性肝病有关，哪些则无关。 的 与ALD相关的异常将被认为是可疑的， ALD的发生机制有待进一步研究。 预防措施将 进行测试，以确定哪些机制涉及的治疗 干预 研究的机制包括：1）能量代谢， 在体肝脏31 P MRS与肝脏中的O2张力相关 长期酒精喂养期间; 2）亚油酸/花生四烯酸 代谢产物和抑制剂的GL色谱和HPLC代谢 花生四烯酸代谢酶的形态测定; 3）Ito的形态测定 使用电子技术与肝纤维化相关的细胞活化 琥珀酸脱氢酶组织化学 3区肝细胞中增加的渗透性;和5）维生素A代谢 在ALD。

Objectives: To determine the mechanism of alcoholic liver disease so that dietary interventions and preventive medicine will make it possible to minimize this disease. Specific Aims: To produce alcoholic liver disease which closely resembles human ALD including fatty change, inflammation, necrosis, and fibrosis of the liver in rats fed defined diets and alcohol by continuous intragastric feeding. This dietary regimen is modified in a way that by changing only one dietary ingredient, i.e. fat, no ALD lesion develops when the rats are fed ethanol. The diet which produces ALD contains 25% of calories derived from corn oil. The diet which prevents ALD substitutes corn oil with tallow (25% of calories). Using these two diet regimens, the one that produces ALD and the one that does not, the rats will be analyzed for the presence of biochemical and morphologic abnormalities in order to identify which abnormalities are associated with ALD and which are not. The abnormalities associated with ALD will be considered suspect as involved in the mechanism of ALD and will be studied further. Preventive measures will be tested to determine which mechanisms are involved by therapeutic intervention. Mechanisms to be studied include: 1) energy metabolism of the liver using 31P MRS in vivo correlated with 02 tension in the liver during chronic alcohol feeding; 2) linoleic acid/arachidonic acid metabolism using GL chromatography and HPLC of metabolites and inhibitors of arachidonate metabolizing enzymes; 3) morphometric determination of Ito cell activation associated with liver fibrosis using the electron microscope; 4) succinic dehydrogenase histochemistry for alcohol-induced increased permeability in zone 3 liver cells; and 5) vitamin A metabolism in ALD.