三种小鼠酒精性肝病短期模型的评价  

Evaluation on three short-term animal models of alcoholic liver disease

作　　者：张译文 李昱锦 胡冰芳 黄民[1] 

机构地区：[1]中山大学药学院,临床药理研究所,广东广州510006

出　　处：《药学学报》2018年第2期236-243,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81320108027);高等学校学科创新引智计划(111计划)资助项目(B16047).

摘　　要：酒精性肝病分为脂肪肝、脂肪型肝炎、肝纤维化和肝硬化;严重情况下会发展成肝癌,如今已经成为继病毒性肝炎之后我国第二大肝病。目前,针对上述疾病的动物模型较为繁杂,诱导指标单一,且与临床指标有较大差异。其中,有3种短期模型应用较为普遍,分别为酒精灌胃诱导的急性肝损伤、短期液体饲料诱导的脂肪型肝炎(Gao-binge模型)及酒精液体饲料联合四氯化碳注射诱导的肝纤维化模型。在本研究中,充分讨论了上述3种短期模型的病理指标,并根据参考文献和临床数据对其进行有效评价。结果发现,所有模型的造模组肝重比均明显高于对照组(P<0.05),病理切片证实造模组有空泡样病变和脂质沉积。然而,对血清生化指标和炎症因子的诱导程度有较大差异。在急性肝损伤模型中,肝脏IL-6和CCL2的m RNA水平大幅下调(P<0.05),与单次过量饮酒患者的全血基因表达结果相似,而血清生化指标无变化趋势。Gao-binge模型中,造模组血清ALT、AST和TG水平显著上升(P<0.05),肝脏TG含量、IL-6和CCL2的m RNA表达水平也明显上调(P<0.05),与临床脂肪型肝炎患者的病理指标一致。在肝纤维化模型中,除造模组出现明显的汇管区纤维化和少量脂滴聚集外,血清生化指标和炎症水平均无显著性变化。综上,3种动物模型代表了酒精性肝病的各个阶段。其中,Gao-binge模型的建模方法相对简单,得到的指标较为全面,且与临床指标变化趋势相似,有可能成为研究酒精性肝病的理想动物模型。此外,本研究还发现CCL2在酒精性肝病的不同阶段基因表达水平不同,能较好区分各阶段酒精性肝病,可作为潜在生物标记物。Alcoholic liver disease （ALD） includes a spectrum of disorders ranging from asymptomatic steatosis, alcoholic steatohepatitis （ASH）, fibrosis and cirrhosis. According to epidemical statistics, ALD has been ranked as the second major cause of liver diseases in China. Many animal models have been made in the study of potential therapies. However, in most of the models, the pathological changes are not always consistent with those in patients. There are three widely used short-term animal models of ALD：the acute alcoholic liver injury model, Gao-binge steatohepatitis model and CCl4-alcohol diet induced liver fibrosis model. In this study, we evaluated the pathological responses of these models and compared the responses with the clinical parameters. The liver/body weight ratio was increased and liver histological lesions were induced in alcoholic groups in the three models, while the levels of biochemical parameters and inflammatory factors were affected by different type of treatments. In the acute alcoholic model, the mRNA levels of interleukin-6 （IL-6） and C-C motif chemokine receptor-2 （CCL2） were surprisingly decreased, which was consistent with the transcriptome profile in patients （P 〈 0.05）, but the serum ALT and AST level, were not changed. In Gao-binge model, both AST/ALT and triglyceride levels were significantly induced by alcoholic consumption （P 〈 0.05）, along with the gene expression levels of hepatic IL-6 and CCL2 （P 〈 0.05）. These data were similar in tendency to the pathological indicators of hepatitis patients. In liver fibrosis model, although histological section indicated obvious fibrotic lesion and little lipid accumulations, other indexes were barely changed. In conclusion, the Gao-binge model induced similar pathological patterns to those of steatohepatitis patients. Gao-binge model might be ideal for study of ALD, especially alcoholic steatohepatitis. In addition, we also found that hepatic gene expression of CCL2 was impacted differently at various stage

关 键 词：酒精性肝病 CC族趋化因子2 白介素6 

分 类 号：R965[医药卫生—药理学]