肝细胞生长因子抗肝纤维化作用及对MMP-1,TIMP-1表达的影响

Effects of hepatocyte growth factor on fibrosis and hepatic expression of MMP-1 andTIMP-1

目的:研究肝细胞生长因子对实验性大鼠肝纤维化的防治作用,及其对大鼠肝脏基质金属蛋白酶1(MMP-1)抑制因子1(TIMP-1)表达的影响,探讨HGF抗肝纤维化作用的可能机制.方法:将Wistar♂大鼠80只随机分为正常对照组(A组,16只),肝纤维化模型组I(B组,54只),HGF治疗组I(C组,10只),采用CCl4复合因素造模,治疗组于造模同时予HGF0.5μg/Kg,ip,qd,6wk末造模成功处死C组大鼠,同时随机处死A组及B组大鼠各6只;对B组剩下大鼠行二次随机分组为模型对照组II(D组,12只),HGF治疗组II(E组,10只),E组于第7周开始给予HGF治疗,10wk末处死大鼠.检测大鼠肝功能,血清透明质酸(HA),层粘蛋白(LN),III型前胶原(PcIII),IV型胶原(CIV);免疫组化法检测肝组织MMP-1,TIMP-1的表达.结果:C组与B组比较,ALT,AST,HA,LN,CIV,PcIII均显著降低(P<0.01),MMP-1活性升高(0.25±0.02,vs0.22±0.05,P<0.05);TIMP-1活性明显降低(0.34±0.05,vs0.45±0.05,P<0.01).E组与D组相较,MMP-1活性变化无显著性,TIMP-1活性有明显降低(0.31±0.07,vs0.42±0.06,P<0.01).结论:肝细胞生长因子对肝纤维化有明显的防治作用,并可能通过促进MMP-1的活性或抑制TIMP-1活性而促进肝纤维化降解.

AIM:To investigate the effect of hepatocyte growth factor (HGF) on severity of liver fibrosis and hepatic expressions of MMP-1,TIMP-1 and to explore the mechanism of HGF in preventing liver fibrosis in rats. METHODS:Eighty male Wistar rats were randomly divided into normal control group (Group A, 16 rats), liver fibrosis model group (Group B, 54 rats) and HGF therapy group (Group C, 10 rats). The liver fibrosis model was induced by administration CCl4 intraperitoneally.Rats in Group C had been administered HGF for six weeks and were sacrificed afterwards. Eight rats from each of group A and B were randomly sacrificed on week 6 simultaneously as that in group C. The remaining rats in-group B were randomly further subdivided into liver fibrosis model group (Group D, 12 rats) and HGF therapy group (Group E, 10 rats),HGF was administered to rats in group E on week.7.All rats in group D and E were sacrificed on week 10. Liver function and levels of serum hyaluronic acid (HA), mucin (LN), collegen type IV (CIV), procollagen III (PCIII) were tested; the expression of MMP-1 and TIMP-1 were determined by immunohistochemical staining and analyzed by computer. RESULTS:Compared with Group B, the serum levels of ALT, AST, HA, LN, CIV, PCIII in Group C were significantly reduced (P <0.01), MMP-1 activity was slightly increased (0.25±0.02, vs 0.22±0.05, P <0.05),TIMP-1 activity was markedly reduced (0.34±0.05, vs 0.45±005, P <0.01).TIMP-1 activity in Group E (0.31±0.07) was also markedly reduced in comparison with Group D ( 0.42±0.06) (P <0.01).CONCLUSIONS:HGF has obvious effect in preventing develop- ment of liver fibrosis; it might facilitate degradation of hepatic fibrosic tissue via increasing the MMP-1 activity and or inhibiting TIMP-1 activity.