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探讨Cenicriviroc(CVC)对硫代乙酰胺(TAA)所致大鼠肝纤维化的治疗作用。SD雄性大鼠66只被随机分为模型对照组和CVC治疗组。各组大鼠于同日开始腹腔注射TAA 30mg/Kg,3次/周,连续8周;另设空白对照组。治疗组分别在TAA诱导肝纤维化不同时间,按30mg·kg-1·d-1灌胃给药,包括:与TAA同日开始给CVC,连续8周(1B组);TAA腹腔注射4周后,给予CVC,连续4周(2B组)和TAA腹腔注射8周停用后,再给予CVC,4周(3B组)。治疗结束后,检测血清中生化指标,留取肝组织,行HE和苦味酸天狼星红溶液染色,观察肝脏病理学改变,并进行肝纤维化定量分析。同时,以qRT-PCR检测CVC对培养肝星状细胞(HSC)表达α-平滑肌肌动蛋白(α-SMA)和胶原蛋白I(collagen I)的直接作用。与模型组比,早、中期CVC治疗(1B组和2B组)显著降低肝纤维化大鼠增高的肝脏系数(P<0.05)和血清中异常升高的天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)(P<0.01),病理组织学检查结果表明,1B组和2B组大鼠肝纤维组织增生和肝组织炎症活动度较模型组均有显著的改善(P<0.05),其肝组织中胶原纤维面积显著降低(P<0.01),但是CVC对已形成的肝硬化(3B组)无显著改善作用。体外实验显示,CVC可以直接抑制HSC胶原蛋白I mRNA表达(P<0.05),但α-SMA mRNA表达与对照组无明显差异。CVC具有明显抑制肝纤维化形成作用,但对已形成的肝硬化缺乏逆转作用。
To investigate the therapeutic effect of Cenicriviroc (CVC) on hepatic fibrosis induced by thioacetamide (TAA) in rats. 66 SD male rats were randomly divided into model control group and CVC treatment group. The rats in each group were injected intraperitoneally with TAA 30mg / Kg on the same day for 3 times / week for 8 weeks. Another blank control group was established. The rats in the treatment group were intragastrically administrated with 30mg · kg-1 · d-1 at different times of TAA-induced hepatic fibrosis, including CVC on the same day with TAA for 8 weeks (group 1B), TAA 4 weeks after intraperitoneal injection , CVC for 4 weeks (group 2B), and TAA for 8 weeks. CVC was given for 4 weeks (group 3B). After the treatment, the serum biochemical indexes were detected, the liver tissues were collected and stained with hematoxylin-eosin and picric acid Sirius red staining to observe the pathological changes of the liver and quantitatively analyze the liver fibrosis. Meanwhile, the direct effect of CVC on α-smooth muscle actin (α-SMA) and collagen I in cultured hepatic stellate cells (HSCs) was detected by qRT-PCR. Compared with the model group, early and mid-term CVC treatment (group 1B and group 2B) significantly reduced hepatic coefficient (P <0.05) and abnormally elevated serum aspartate aminotransferase (AST) (P <0.01). The results of histopathological examination showed that the hepatic fibrosis and hepatic inflammation activity of group 1B and group 2B were significantly improved than that of model group (P <0.05) The area of collagen fibers in liver tissue was significantly decreased (P <0.01), but CVC had no significant effect on the formation of cirrhosis (Group 3B). In vitro experiments showed that CVC can directly inhibit HSC collagen I mRNA expression (P <0.05), but α-SMA mRNA expression in the control group no significant difference. CVC has significantly inhibited the formation of hepatic fibrosis, but the formation of cirrhosis has no reversal effect.