Tanshinone ¢ò A On The Protection Of Experimental Liver Injury And Its Mechanism

Objective:To research on the protection of Tanshinoneâ…¡A(TSN) on acute and chronic liver injury,and investigate its mechanism.Methods:Based on the existing research results and with reference to research method of herbal pharmacology,the author builded animal models respectively with carbon tetrachloride(CCl₄),D-galactosamine (D-GalN) and concanavalin A(ConA) induced acute and chronic liver injuries in this study.The author adopted various detection methods of flow cytometry,enzyme immunoassay technique(ELISA),immunohistochemical technique,image quantitative analysis,hematoxylin-exsin and masson staining,and observed various indexes including T lymphocyte subsets CD3⁺,CD4⁺ and CD8⁺ ratios,cytokines including tumor necrosis factor alpha(TNF-α),interferon-gamma(IFN-γ,),interleukin-2(IL-2), interleukin-4(IL-4),interleukin-10(IL-10) and transforming growth factor-β1(TGF-β1),oxidative stress parameters Malondialdehyde(MDA) and the Superoxide Dismutase(SOD),liver function indexes including plasma alanine aminotransferase(ALT),aspartate aminotransferase (AST),Alkaline Phosphomonoesterase(ALP),total protein(TP), albumin(Alb),total bilirubin(T.Bili) and direct bilirubin(D.Bili) levels, and other indexes hydroxyproline(Hyp),nitric oxide(NO) and alpha-sooth muscle actin(α-SMA).Results:In this study,TSN is found to significantly reduce plasma ALT and AST levels in mice with CCl₄ and D-GalN induced liver injury.TSN increases liver tissue SOD and reduces MDA in mice with D-GalN induced liver injury.TSN significantly reduces plasma ALT,AST,ALP, T.Bili and D.Bili levels and liver tissue NO,Hyp and MDA,and increases plasma TP and Alb and liver tissue SOD in rats with CCl₄ induced liver fibrosis.TSN is found to significantly improve degree of liver injury and collagen fibers hyperplasia,and reduce expression ofα-SMA.TSN is also found to significantly reduce plasma ALT and AST levels in mice with concanavalin A(ConA)-induced immune-mediated liver injury.TSN increases T lymphocyte subset CD3⁺,CD4⁺ and CD8⁺ ratios which are downregulated in the liver injury model.Also,TSN significantly reduces inflammatory cytokines,including interleukin-2 (IL-2),interleukin-4(IL-4),interferon-gamma(IFN-γ) and tumor necrosis factor alpha(TNF-α),while elevates anti-inflammatory cytokine interleukin-10(IL-10).Conclusion:These findings suggest that TSN has protective effects against acute and chronic liver injuries induced by multifactor.The mechanism may be:(1) antioxygen radicals,(2)reduction of NO and alleviation of the inflammatory cell infiltration,(3)down-regulated expression of TGF-β1 andα-SMA,and inhibition of activation of HSC, (4) inhibition of release of inflammatory cytokines IL-2,IL-4,TNF-αand IFN-γ,while elevation of anti-inflammatory cytokine IL-10,(5)increase of the ratio of peripheral blood T lymphocyte subsets CD3⁺,CD4⁺ and CD8⁺ and regulation of the balance of them.Innovation:The author first systematically observed TSN protection against liver injury in different aspects and levels,and found that TSN has a very good therapeutic effect,while utilized research means of modern molecular biology and illustrated its mechanism at the cellular and molecular levels.It is the first report about the TSN pretection against ConA-induced immune-mediated liver injuty through regulations of activitions of T lymphocyte subsets and inflammatory and antiinflammatory cytokines.It is also the first report about TSN downregulated expression ofα-SMA,inhibition of activation of HSC and reduction of ECM production so as to prevent formation of liver fibrosis.