Molecular analysis of the mechanism of fibrosis in alcoholic liver disease

在酒精性肝损伤纤维化的发病机制中，胶原蛋白可能在其过程中起关键作用。我们在本研究中假设IV型胶原可能是血管生成转化的标志。而在纤维化过程中，I型胶原蛋白以改变为主，很难检测到IV型胶原蛋白组分表达的微小变化。用细胞培养系统观察IV型胶原蛋白的表达可能更可取。在肝纤维化的另一方面，一氧化氮（NO）、一氧化碳等几种生物活性物质参与肝硬化的病理生理。这些物质具有血管活性、细胞因子调节剂和细胞增殖等多方面的作用，并被推测以不同的方式参与各种病理机制。在本研究中，我们研究了氮氧化物对外源性内毒素负荷的影响，以及几种慢性肝损伤模型肝脏中一氧化氮合酶（NOS）和血红素加氧酶（HO） mRNA表达的变化。采用液体乙醇饲料诱导酒精性大鼠ALD模型，采用硫乙酰胺治疗肝硬化大鼠8周。HO-I mRNA在两种模型中均较对照大鼠增强，且在Northern分析中肝硬化大鼠表达更强烈。脂多糖（LPS）刺激ALD和肝硬化动物ho - 1 mRNA的表达。在NOS mRNA表达方面，两种模型的eNOS表达均无明显变化，LPS处理后的jNOS表达虽不稳定，但在Northern和RT-PCR分析中均检测到。结论：1)HO- i mRNA在慢性肝损伤中被诱导，并在LPS刺激下表达上调；2)推测NO系统对HO系统的反应可能受到反向调控。在慢性肝损伤过程中，生物物质及其合酶随原发疾病的不同表现出不同的动态变化。少

In the pathogenesis of fibrosis in alcoholic liver injury, collagen may play a critical role in its process. We hypothesized in this study that type IV collagen might be a marker of angiogenetic transformation of sinusoidal structure. However, type I collagen dominantly changed in the fibrotic process, it was difficult to detect the small change of the expression of type IV collagen component.It may be preferable to use the cell culture system for the observation of the expression of type IV collagen.In another aspect of liver fibrosis, several biological active substances, such as, nitric oxide (NO), carbon monoxide are involved in the pathophysiology of liver cirrhosis. These substances have multiple aspects relating to vasoactivity, cytokine-modulator and cell-proliferation etc., and are speculated to be contributing to various pathological mechanisms in a different manner. In this study, we investigated the changes of Nox on the loading of external endotoxin, and the mRNA expressio … More n of nitric oxide synthase (NOS) and heme oxygenase (HO) in the liver in several models of chronic liver injury. Alcoholic model (ALD) was induced by the administration of a liquid ethanol diet, and in cirrhotic model, rat was treated with thioacetamide for 8 weeks. HO-I mRNA was enhanced in both models comparing with control rat, and the expression was more intense in cirrhosis in the Northern analysis. Lipopolysaccharide (LPS) stimulated the HO-I expression of mRNA in ALD and cirrhotic animals. As to NOS mRNA expression, there were no significant changes in eNOS expression in both models, and jNOS was , not constantly, but detected in Northern and RT-PCR analysis, by LPS treatment.Conclusion : 1) HO-I mRNA was induced in chronic liver injury, and was up-regulated by LPS stimulation, 2) the response of NO system was speculated to be counter-regulated toward HO system. In the process of chronic liver injury, biological substances and their synthase show different dynamics dependent of the primary disease. Less