丹参酮ⅡA对实验性肝损伤的保护作用及其机制探讨
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摘要
目的:研究丹参酮ⅡA(tanshinoneⅡA,TSN)对急慢性肝损伤的保护作用,并探讨其作用机制。
方法:在借鉴已有关于TSN抗肝损伤文献报道的基础上,参照中药药理研究方法,分别从化学性、免疫性的急慢性肝损伤两个角度建立CCl_4和D-GalN诱导的小鼠急性肝损伤、CCl_4诱导的大鼠慢性肝损伤(肝纤维化)以及ConA诱导的小鼠免疫性肝损伤四种损伤机制不同的动物模型。采用流式细胞术、酶联免疫吸附技术(ELISA)、免疫组织化学技术、图像定量分析、苏木素-伊红(HE)和马森(Masson)染色等检测方法。观察T淋巴细胞亚群CD3~+、CD4~+、CD8~+比率,细胞因子TNF-α、IFN-γ、IL-2、IL-4、IL-10和TGF-β1,氧化应激指标MDA和SOD,肝功能血清学指标ALT、AST、ALP、TP、Alb、T.Bili和D.Bili,以及α-SMA、Hyp和NO多种指标进行研究。
结果:TSN可显著减低CCl_4所致急性肝损伤小鼠血清ALT和AST;TSN可显著减低D-GalN所致急性肝损伤小鼠血清ALT和AST,提高肝组织中SOD的活性并降低MDA;TSN可显著降低CCl_4所致肝纤维化大鼠血清ALT、AST、ALP、T.Bili和D.Bili及肝组织中NO、Hyp和MDA,提高血清TP、Alb和肝组织中SOD,明显改善肝组织损伤程度及胶原纤维增生,减少TGF-β1和α-SMA的表达;TSN可显著减低ConA所致急性肝损伤小鼠血清ALT和AST,提高外周血中CD3~+、CD4~+、CD8~+比率,并降低TNF-α、IFN-γ、IL-2、IL-4同时提高IL-10。
结论:TSN对多种因素所致的急慢性肝损伤具有保护作用,其作用机制可能为:(1)抗氧自由基损伤;(2)减少NO含量,减轻炎症细胞浸润;(3)下调TGF-β1和α-SMA的表达,抑制HSC的激活;(4)抑制炎性细胞因子同时提高抗炎性细胞因子的释放,减轻细胞因子对肝脏的损伤;(5)提高外周血T淋巴细胞亚群CD3~+、CD4~+、CD8~+细胞的比率,调节T细胞亚群问相互平衡和制约。
创新:本研究首次从不同层次、不同方位较为系统地观察TSN对肝损伤的保护作用,发现TSN对多因素所致实验性肝损伤均显示出较好的治疗效果。同时,应用现代分子生物学研究手段并从细胞分子水平阐明了其作用机制。本研究首次报道TSN通过调节T淋巴细胞各亚群的活性及相互间的制约参与对ConA介导的免疫性肝损伤的保护;首次报道各细胞因子在TSN治疗ConA介导的免疫性肝损伤中的不同作用;首次报道TSN通过下调α-SMA的表达,抑制HSC的活化,减少ECM合成,从而阻止纤维化的形成。
Objective:To research on the protection of TanshinoneⅡA(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(CCl_4),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 CCl_4 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 CCl_4 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.
方法:在借鉴已有关于TSN抗肝损伤文献报道的基础上,参照中药药理研究方法,分别从化学性、免疫性的急慢性肝损伤两个角度建立CCl_4和D-GalN诱导的小鼠急性肝损伤、CCl_4诱导的大鼠慢性肝损伤(肝纤维化)以及ConA诱导的小鼠免疫性肝损伤四种损伤机制不同的动物模型。采用流式细胞术、酶联免疫吸附技术(ELISA)、免疫组织化学技术、图像定量分析、苏木素-伊红(HE)和马森(Masson)染色等检测方法。观察T淋巴细胞亚群CD3~+、CD4~+、CD8~+比率,细胞因子TNF-α、IFN-γ、IL-2、IL-4、IL-10和TGF-β1,氧化应激指标MDA和SOD,肝功能血清学指标ALT、AST、ALP、TP、Alb、T.Bili和D.Bili,以及α-SMA、Hyp和NO多种指标进行研究。
结果:TSN可显著减低CCl_4所致急性肝损伤小鼠血清ALT和AST;TSN可显著减低D-GalN所致急性肝损伤小鼠血清ALT和AST,提高肝组织中SOD的活性并降低MDA;TSN可显著降低CCl_4所致肝纤维化大鼠血清ALT、AST、ALP、T.Bili和D.Bili及肝组织中NO、Hyp和MDA,提高血清TP、Alb和肝组织中SOD,明显改善肝组织损伤程度及胶原纤维增生,减少TGF-β1和α-SMA的表达;TSN可显著减低ConA所致急性肝损伤小鼠血清ALT和AST,提高外周血中CD3~+、CD4~+、CD8~+比率,并降低TNF-α、IFN-γ、IL-2、IL-4同时提高IL-10。
结论:TSN对多种因素所致的急慢性肝损伤具有保护作用,其作用机制可能为:(1)抗氧自由基损伤;(2)减少NO含量,减轻炎症细胞浸润;(3)下调TGF-β1和α-SMA的表达,抑制HSC的激活;(4)抑制炎性细胞因子同时提高抗炎性细胞因子的释放,减轻细胞因子对肝脏的损伤;(5)提高外周血T淋巴细胞亚群CD3~+、CD4~+、CD8~+细胞的比率,调节T细胞亚群问相互平衡和制约。
创新:本研究首次从不同层次、不同方位较为系统地观察TSN对肝损伤的保护作用,发现TSN对多因素所致实验性肝损伤均显示出较好的治疗效果。同时,应用现代分子生物学研究手段并从细胞分子水平阐明了其作用机制。本研究首次报道TSN通过调节T淋巴细胞各亚群的活性及相互间的制约参与对ConA介导的免疫性肝损伤的保护;首次报道各细胞因子在TSN治疗ConA介导的免疫性肝损伤中的不同作用;首次报道TSN通过下调α-SMA的表达,抑制HSC的活化,减少ECM合成,从而阻止纤维化的形成。
Objective:To research on the protection of TanshinoneⅡA(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(CCl_4),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 CCl_4 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 CCl_4 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.
引文
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