Inhibitory effects of rapamycin on the different stages of hepatic fibrosis

AIM:To investigate and compare the inhibitory effects of rapamycin in the different stages of liver fibrosis.METHODS:We performed bile duct ligation(BDL)in male Wistar rats(n=24).The experimental rats were classified into four groups:the BDL+/Rapa-group(untreated control,n=4),the BDL+/Rapa+group(treated14 d after BDL,n=8),the BDL+/Rapa++group(treated on the day after BDL,n=8),and the BDL-/Rapagroup(un-treated,sham-operated control,n=4).The BDL+/Rapa+and BDL+/Rapa++groups were administered rapamycin(2 mg/kg)for 28 d.The liver tissues were tested by immunohistochemical staining forα-smooth muscle actin(α-SMA)and cytokeratin.RESULTS:The liver mRNA levels of transforming growth factor(TGF)-β1 and platelet-derived growth factor(PDGF)were measured using the polymerase chain reaction.The protein levels of liver p70s6K and p-p70s6k were determined using Western blotting.α-SMA expression was lowest in the BDL+/Rapa++group.TGF-β1and PDGF expression levels in the rapamycin-treated group were lower than those in the un-treated group and higher than those in the control groups(TGF-β1:0.23±0.00 vs 0.34±0.01,0.23±0.0 vs 0.09±0.00,P<0.0001;PDGF:0.21±0.00 vs 0.34±0.01,0.21±0.0 vs 0.09±0.00,P<0.0001).The p70s6k and p-p70s6k levels decreased in the treated groups and were lowest in the BDL+/Rapa++group(p70s6k:1.05±0.17 vs 1.30±0.56,0.40±0.01 vs 1.30±0.56,P<0.0001;p-p70s6k:1.40±0.5 vs 1.67±0.12,0.70±0.01 vs 1.67±0.12,P<0.0001).CONCLUSION:The results of our study indicate that rapamycin has inhibitory effects on liver fibrosis,and the treatment is most effective in the early stages of fibrosis.