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银杏叶提取物治疗大鼠肝纤维化的机制研究
【作者】 时昭红；
【导师】 涂晋文；
【作者基本信息】 湖北中医学院 ， 中医内科学， 2006， 博士
【摘要】 肝纤维化不论何种病因，细胞外基质(exacellular matrix，ECM)增加是其特征，表现为ECM数量增加和／或成分改变。其发展的细胞和分子机制的阐明，为这一疾病的防治提供了依据。几乎所有的临床和动物实验研究均提示纤维化的发生发展与氧化应激(oxidative stress，OS)、氧自由基损伤、脂质过氧化等有关。研究证实，抗氧化剂可通过抑制肝星状细胞(hepatic stellate cell，HSC)活化和增殖，减少ECM的合成，从而起到预防和减轻肝纤维化的作用。 现代研究发现，银杏叶所含主要成分银杏黄酮甙能有效地清除体内有毒过氧自由基的作用，银杏苦内酯因其有高度专属性抗血小板活化因子(PAE)的作用而引起国际医学界的关注。近年来，欧洲专题报道银杏叶中存在活性成分Bioparyl(一种抗氧化剂)，可调节核糖核酸酶的活性，防止／逆转各组织纤维变性，因此推测银杏叶有抗氧化应激作用，可促进肝纤维化的恢复。 迄今为止对银杏叶提取物抗肝纤维化的作用及其机制缺乏系统深入的研究，国内外尚无银杏叶提取物治疗实验性肝纤维化的研究报道。为此，我们进行实验研究，利用四氯化碳诱导大鼠肝纤维化模型，采用银杏叶提取物对其进行治疗，观察银杏叶提取物对肝纤维化大鼠一般情况及肝功能指标、肝脏组织病理学的影响；对肝组织中氧化指标MDA的含量，SOD、GSH-PX的活性的影响；对肝纤维化大鼠细胞因子TGF-β1和Activill A表达的影响；对肝纤维化大鼠肝星状细胞活化及肝细胞凋亡的影响；以及对肝纤维化大鼠肝组织MMP-1及TIMP-1基因表达的影响。希望通过本组实验研究银杏叶提取物对大鼠肝纤维化的治疗作用，并从分子水平、细胞水平以及氧化应激、细胞外基质降解方面探讨银杏叶提取物治疗大鼠肝纤维化的作用机制，为临床合理应用银杏叶制剂提供参考依据。整个实验共分为6个部分： 1 银杏叶提取物对肝纤维化大鼠一般情况及肝功能指标的影响 目的：利用银杏叶提取物对肝纤维化大鼠进行治疗，观察治疗过程中肝纤维化大鼠的一般情况及其血清肝功能指标的变化。 方法：48只雄性SD大鼠被随机分为四组：正常组、肝纤维化模型组、秋水仙碱
【Abstract】 Hepatic fibrosis is predominantly characterized by excessive accumulation of extracellular matrix （ECM） components in the liver, caused by an imbalance between synthesis and degradation of ECM. Up to now, no effective treatment of hepatic fibrosis is available for clinical use, in particular, no method for enhancing; degradation and resolution of these deposited ECM. and reversing hepatic fibrosis. Ginkgo Biloba extract（EGB） is an extract from green leaves of the Ginkgo biloba tree. EGB has been shown to have a SOD-like activity and hydroxyl radical scavening activity. Accordingly, we guess EGB can inhibit oxidative stress and hasten recovery of hepatic fibrosis.So far, there is no systemic research in treating hepatic fibrosis by Ginkgo biloba extract（EGB）. Therefore, we use EGB treating CCl4-induced hepatic fibrosis, and investigate the effect of general state of health, indication of liver function and histopathology on hepatic fibrosis’s rat. Also ,we explore the effect of the oxidative indication such as MDA, SOD and GSH-Px, the express of TGF-β1 and Activin A , the activation of HSC, the apoptosis of liver cell, and the gene express of MMP-1 and TIMP-1. From the experiment, we will investigate the therapia effect of EGB on fibrosis’s rat, and explore the treated mechanism from oxidative stress, molecular level, cellular level and degradation of ECM by the way. The experiment was divided into six part.Part 1: The effect of Ginkgo biloba extract on general state of health and indication of liver function in hepatic fibrosis’s rat.Objective: To investigate the change of general state of health and indication of liver in the course of treating hepatic fibrosis’s rat. Methods: The study was conducted in 48 adult male SD rats randomized into 4 groups: normal group, model group, treatment group and colchicin group. Except the rats in the normal group, others were inflicted with liver fibrosis by administration of CCL4 for 8 weeks. Then, the rats of normal group and model group were sacrificed. Blood samples were collected for determination of ALT. AST. AKP and ALB. Those rats in the treatment