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目的:采用复合因素建立大鼠肝纤维化模型,并对其肝脏纤维化病变和相关指标进行动态观察。方法:雄性Wistar大鼠随机分为对照组和肝纤维化模型组,模型组大鼠每周2次乙醇灌胃、猪血清腹腔注射、CCl4葵花仔油溶液皮下注射,同时每日喂饲高脂饲料进行联合造模。分别在造模后第2、4、6、7、8、9、10周检测各组大鼠血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、总蛋白(TP)、白蛋白(Alb)、透明质酸(HA)、层粘连蛋白(LN)、转化生长因子β1(TGF-β1)、基质金属蛋白酶(MMP-2、MMP-9、MMP-13)及其抑制物(TIMP1、TIMP-2)水平,并观察肝脏病理病变。结果:从第2周起,模型组大鼠血清ALT、AST水平开始升高,各时间点与对照组比较均具有显著性差别;血清HA和LN水平逐渐增高,第7~10周与对照组比较均具有显著性差别;血清MMP-2水平逐步升高,第4、6~10周与对照组相比均具有显著性差别;血清MMP-13水平从第6周起逐渐降低,第9和10周时显著低于对照组;血清TIMP-1和TIMP-2水平随造模时间延长逐步升高,TIMP-1在第4,6~10周与对照组相比均具有显著性差别,TIMP-2在第7~10周显著高于对照组;模型组大鼠各时间点血清TGF-β1水平均显著高于对照组。病理组织学检查显示,第6周时,模型组大鼠肝脏细胞广泛性空泡变性,汇管区成纤维细胞增生,肝小叶间隔可见胶原纤维沉积,出现典型的肝纤维化改变;到第8周时,形成典型的假小叶,肝硬化形成。结论:采用酒精灌胃,猪血清腹腔注射,喂饲高脂饲料,并结合CCl4皮下注射6周后,可成功建立大鼠肝纤维化模型;HA、LN、TGF-β1、MMP-2、TIMP-1和TIMP-2等可作为较好反映大鼠肝纤维化病变的无创伤化血清学指标。
OBJECTIVE: To establish a model of hepatic fibrosis in rats by composite factors, and to observe the pathological changes of liver fibrosis and related indicators. Methods: Male Wistar rats were randomly divided into control group and hepatic fibrosis model group. Rats in model group were intragastrically administered with ethanol twice a week, intraperitoneal injected with porcine serum, and CCl4 sunflower oil solution subcutaneously. Meanwhile, Feed joint modeling. The serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), white (Alb), hyaluronic acid (HA), laminin (LN), transforming growth factor-β1 (TGF-β1), matrix metalloproteinase (MMP-2, MMP-9, MMP- TIMP1, TIMP-2) levels, and observe the pathological changes of liver. Results: Serum levels of ALT and AST in model group began to increase from the second week, and there was a significant difference between the two groups at each time point. The level of serum HA and LN increased gradually. Compared with the control group The level of serum MMP-2 gradually increased, and there was a significant difference between the 4th and 6th to 10th weeks and the control group. The serum MMP-13 level decreased gradually from the 6th week, while the 9th and The levels of TIMP-1 and TIMP-2 in serum increased gradually with the prolongation of modeling time. TIMP-1 was significantly different from the control group at the 4th, 6th to 10th weeks -2 was significantly higher in the 7th to 10th weeks than that in the control group. The levels of serum TGF-β1 in the model group at each time point were significantly higher than those in the control group. Histopathological examination showed that at week 6, the rat hepatocytes in the model group were extensively degenerated, the fibroblasts were proliferated in the portal area, collagen fibers were deposited at the interlobular septa, and typical hepatic fibrosis was observed. By week 8 When the formation of a typical false lobule, cirrhosis of the formation. Conclusion: The rat model of hepatic fibrosis was successfully established by intragastric administration of alcohol, intraperitoneal injection of swine serum, feeding of high-fat diet and subcutaneous injection of CCl4 for 6 weeks. The expressions of HA, LN, TGF-β1, MMP-2, -1 and TIMP-2 can be used as noninvasive serum markers to better reflect the pathological changes of rat liver fibrosis.