The Effect Of Rosiglitazone, A PPARγ Receptor Agonist, On The LPS Induced Acute Hepatic Injury

Subject:To investigate the effect of Rosiglitazone,a PPARγ,receptor agonist,on the LPS-induced acute liver injury and LPS induced MAPK,STAT and NF-kB signal transduction.Methods:The experiment(Exp)1.The male Kunming mice were divided randomly into three groups. (1)control:0.9%Sodium Chloride and 18%DMSO,0.2ml,i.p..(2)LPS group:LPS 5mg/kg,i.p..(3) Rosiglitazone+LPS group:Rosiglitazone 6mg/kg,i.p.LPS(5mg/kg)was injected though peritoneal after 1h of Rosiglitazone administration.The blood was gathered from eye vein and livers were excised with carbrital anaesthesia after LPS or 0.9%Sodium Chloride injected at 0.5h,1.5h and 6.0h for ALT, MDA,TNF-α,GSSG,GSH and GSH/GSSG assays for each group.Exp 2.The experimental mice were divided randomly into two groups.(1)control:the mixture of 0.9%Sodium Chloride and 18%DMSO,0.2ml, i.p..(2)Rosiglitazone group:Rosiglitazone 6mg/kg,i.p.India ink 1:5 diluted with germ free physiological saline was injected into the vail vein in each group after 1h of Rosiglitazone or 0.9%Sodium Chloride administration..Calculate phagocytic index k and its correctionα.Exp 3(1).The experimental mice were divided randomly into three groups.(1)control:0.9%Sodium Chloride and 18%DMSO,0.2ml,i.p..(2) Rosiglitazone group:the treatment was same as the experimentl.(3)Rosiglitazone+LPS group:the treatment was same as the experiment 1.The livers of the first and the second groups were excised in anaesthetic state by carbrital after LPS or 0.9%Sodium Chloride injected at 2h,4h,6h,8h and 10h and the livers of the third group were excised in anaesthetic state by carbrital after ROSI and LPS injected at 0.5h,1.5h and 6h.The protein extracted from livers was assayed for the expression level of PPARγ.Exp 3(2).The animal subgroups and treatments were same as Exp 1.The livers were excised in anaesthetic state by carbrital after LPS or 0.9%Sodium Chloride injected at 0.5h,1.5h and 6h and the protein extracted from livers was assayed for the phosphorylation level of MEK1/2,ERK1/2, p38MAPK,STAT1,STAT3 and expression of HSP 70,NF-kBP65,NF-kBP50,IkB,TLR4,CD14 and PPARγby western blotting analysis.Results:LPS-induced acute liver injury was attenuated significantly by Rosiglitazone.The plasma ALT activity and liver MDA,GSSG contant were decreased remarkably by Rosiglitazone and the GSH and GSH/GSSG assays of liver was increased significantly.In LPS treatment groups,LPS stimulation increased plasma level of TNF-αexpression in the liver,in which the peak values of plasma TNF-αin Rosiglitazone group were much lower than LPS group(p＜0.01).In LPS treatment groups,the expression of PPARγwas decreased.The expression of ERK1/2,p38MAPK,pSTAT3,HSP70,PPARγ,IRAK-M and IkB were heightened significantly and much higher than LPS group in the ROSI pre-stimulation groups,but the expression of MEK1/2,pSTAT1,NF-kBP65,NF-kBP50,TLR4and CD14 was decreased remarkably and much lower than LPS group.Conclusion:Rosiglitazone can activate PPARγreceptors of mice,inhibit the correlate pathway of inflammation though regulate gene expression and signal transducin.So it can affect signal transducin of kupffer cells in the liver,and reduce LPS induced acute liver injury significantly.The anti-inflammatory effect of rosiglitazone may be connected with the inhibition of NF-k B activation.