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目的:二甲基亚硝胺(DMN)诱导的大鼠肝纤维化模型是经典的动物模型,其病理变化与人类肝纤维化发生相类似。普遍观点认为,DMN化学刺激导致肝细胞的损伤,是诱导肝纤维化发生的直接原因,然而其具体的发病机制并不清楚。糖脂代谢异常是脂肪性肝病发生的主要原因之一。糖脂代谢紊乱是否也在DMN诱导肝纤维化模型中占有重要地位,至今尚不清楚。本研究采用全基因芯片技术与生物信息技术相结合方式,研究糖脂代谢异常与DMN诱导肝纤维化之间关系。方法:雄性Wistar大鼠每周前3天连续腹腔注射10 mg·kg~(-1)DMN,持续4周,正常组大鼠给予等量生理盐水。造模2周末,正常组和模型组各5只大鼠做动态观察;造模4周末,剩余大鼠被全部处死,收集肝脏标本。进行肝组织全基因芯片分析,将结果导入生物信息分析软件IPA进行分析。结果:2周模型组与正常组之间、4周模型组与正常组之间共有55个共同差异基因(logRatio>2)。共同差异基因构成的分子网络,主要参与了9条信号通路,它们与炎症、免疫、肝纤维化、脂代谢和血管新生有密切关系。在造模2周(肝纤维化形成期)时,以脂肪酸代谢异常为主要表现;在造模4周(肝硬化形成期)时,以细胞增殖为主要表现。结论:脂肪酸代谢紊乱可能是DMN诱导肝纤维大鼠发病机制之一。
OBJECTIVE: DMN-induced rat liver fibrosis model is a classic animal model with pathological changes similar to those of human liver fibrosis. It is generally believed that the chemical damage of DMN leads to the damage of hepatocytes, which is the direct cause of inducing hepatic fibrosis. However, its specific pathogenesis is not clear. Abnormal glucose and lipid metabolism is one of the major causes of fatty liver disease. Whether glucose and lipid metabolism disorder also plays an important role in DMN-induced liver fibrosis model is still unclear. In this study, the use of all-gene microarray technology and bioinformatics methods to study the relationship between abnormal glucose and lipid metabolism and DMN induced liver fibrosis. Methods: Male Wistar rats were injected intraperitoneally with 10 mg · kg -1 DMN three days before each week for 4 weeks. Rats in normal group were given equal volume of normal saline. At the end of 2 weeks after modeling, 5 rats in normal group and model group were observed dynamically. At 4 weeks after modeling, the remaining rats were sacrificed and liver samples were collected. Whole liver tissue microarray analysis, the results into bioinformatics analysis software IPA analysis. Results: A total of 55 genes (logRatio> 2) were found between the model group and the normal group, and between the 4-week model group and the normal group. Molecular networks of genes that share common differences mainly participate in nine signaling pathways that are closely linked to inflammation, immunity, hepatic fibrosis, lipid metabolism, and angiogenesis. In the model 2 weeks (liver fibrosis formation period), fatty acid metabolism as the main performance; 4 weeks in the modeling (cirrhosis of the formation), the cell proliferation as the main performance. Conclusion: The disorder of fatty acid metabolism may be one of the pathogenesis of DMN-induced hepatic fibrosis in rats.