茵栀黄颗粒治疗雌激素诱导的大鼠胆汁淤积的机制初探
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摘要
目的
探讨茵栀黄颗粒治疗雌激素诱导的大鼠胆汁淤积的作用机制。
方法
用苯甲酸雌二醇(EB,5mg/kg/d)颈部皮下连续注射5d,建立大鼠肝内胆汁淤积模型,对造模成功大鼠随即分为7组,1组为模型组,另6组分别用生理盐水和茵栀黄颗粒灌胃干预7、14、21d,此外,另设1正常对照组,通过胆汁流速、总胆汁流量、血清生化指标、肝脏病理学、免疫组化及Western-blot对各组大鼠进行评价对比。
结果
1.胆汁流速：用EB皮下注射5d后,模型组与正常对照组相比,胆汁流速及总胆汁流量均下降(P<0.05)。生理盐水分别干预7、14、21d时,其与模型组相比,其胆汁流速及总胆汁流量均呈现上升的趋势,但无显著差异。茵栀黄颗粒分别干预7、14、21d时,其与相同天数的生理盐水组相比,其胆汁流速与总胆汁流量均有上升趋势,其中以14、21d增加显著(P<0.05)。
2.血清生化指标：模型组与正常对照组相比,各项血清生化指标呈现上升的趋势,但以DBIL及TBA的升高最为显著(P<0.05)。生理盐水分别干预7、14、21d后,与模型组相比,7d其生化指标无差异(P>0.05)；14d其生化指标上升趋势明显,以DBIL及TBA的升高最为显著(P<0.05)；21d生化指标呈现下降趋势,以TBA下降最为显著(P<0.05)。茵栀黄颗粒分别干预7、14、21d后,与相同天数的生理盐水组相比,14d血清生化指标下降趋势明显,以DBIL及TBA的下降最为显著(P<0.05)；7和21d时无显著变化(P<0.05)
3.肝脏HE染色：正常对照组肝组织结构和细胞形态正常。模型组与正常对照组相比,肝组织出现少量胆管增生,静脉扩张淤血及局部肝细胞坏死变性,少量的炎症细胞浸润。生理盐水分别干预7、14、21d后,与模型组相比,7至14d肝脏病变呈持续加重趋势,21d呈缓解趋势。茵栀黄颗粒分别干预7、14、21d后,与相同天数的生理盐水组相比,其肝脏病变程度均减轻,21d已基本恢复正常。
4.免疫组化：各组大鼠肝脏转运体Mrp2,Oatp2,Bsep及Ntcp均表达于细胞膜上,未见内陷。
5. Western-blot:模型组与正常对照组相比,转运体Oatp2、Ntcp、Bsep及Mrp2表达均显著下降(P<0.05)。生理盐水组分别干预7、14、21d后与模型组相比,转运体Bsep及Mrp2的表达逐渐上升,其中14、21d出现显著性差异(P<0.05)；Oatp2的表达在7、21d时无显著变化(P>0.05),但14d时显著下降(P<0.05)；Ntcp的表达在7、14d时无显著变化(P>0.05),但21d时显著升高(P<0.05)。茵栀黄颗粒分别干预7、14、21d后与相同天数的生理盐水组相比,转运体Bsep的表达均无显著变化(P>0.05)；Mrp2的表达在14d时无显著变化(P>0.05),但7、21d时其表达均显著升高(P<0.05)；Oatp2及Ntcp的表达7d时均无显著变化(P>0.05),但14、21d时表达均显著升高(P<0.05)。
结论
茵栀黄颗粒治疗雌激素诱导大鼠肝内胆汁淤积的作用机制可能与其上调肝细胞膜转运体Oatp2、Ntcp及Mrp2的表达有关,此外,也可能与机体代偿性上调Bsep的表达有关。
Aim
Study on the treatment mechanism of Yin-Zhi-Huang granules to rat cholestasis induced by estrogen
Methods
Rat's intrahepatic cholestasis was induced by estradiol benzoate (EB,5mg/kg/d) via subcutaneous injection for5days, The successfully established experimental intrahepatic cholestasis rats models were randomly divided into7groups, one of them was Model group and other groups were interfered with saline and Yin-Zhi-Huang granules via oral administration for7,14and21days, respectively, no special treatment was required for the Normal group. Then rats were evaluated through comparing bile flow velocity, bile flow volume, biochemical indicator of blood serum, hepatic pathology, immunohistochemistry and western blot.
Results
1. Bile flow experiment: After having been given EB daily subcutaneous injection for5days, bile flow velocity and bile flow volume were decreased compared with Normal group (P<0.05). After saline intervening for7,14and21days, compared with Model group, bile flow velocity and bile flow volume were on the rise, but there was no significant difference. After Yin-Zhi-Huang granules intervening for7,14and21days, bile flow velocity and bile flow volume were on the rise and they were significantly increased (P<0.05) at14and21days compared with the same day's in Saline group.
2. Serum biochemical indexes:Compared with Normal group, serum biochemical indexes were on the rise in Model group, the direct bilirubin and total bile acid was significantly increased (P<0.05). After saline intervening for7,14and21days, compared with Model group, there was no significant difference in7days (P>0.05), serum biochemical indexes were on the rise in14days and the the direct bilirubin and total bile acid was significantly increased (P<0.05). It showed a downward tendency at21days and the total bile acid was significantly decreased (P<0.05). After Yin-Zhi-Huang granules intervening for7,14and21days, compared with the same day's Saline group, serum biochemical indexes had very marked drop trends, the the direct bilirubin and total bile acid were significantly decreased (P<0.05) at14days, there were no significant differences (P>0.05) at7and21days.
3. Liver HE staining: The hepatic tissue structure was normal in Normal group. After EB daily subcutaneous injection for5days, compared with Normal group, there were a small number of bile duct hyperplasia, venous congestion, partial hepatocytes necrosis, and inflammatory cell infiltration in rat liver. After saline intervening for7,14and21days, compared with Model group, the lesions showed a continuous aggravating trend from7to14days, it showed a remission trend at21days. After Yin-Zhi-Huang granules intervening for7,14and21days, the hepatic lesion was much more alleviative than the same day's Saline group, even recovered to normal at21days.
4. Immunohistochemistry showed that the transporter Mrp2, Oatp2, Bsep and Ntcp were all expressed in the liver cell membrane in each group, there was no internalization.
5. Western-blot experiment:Compared with Normal group, the expression of the hepatic Oatp2, Ntcp, Bsep and Mrp2were all significantly decreased (P<0.05). After saline intervening for7,14and21days, compared with Model group, the expression of the transporter Bsep and Mrp2were on the rise, and there was significantly difference at7and14days, the expression of Oatp2had no significant differences (P>0.05) at7and21days, but significantly decreased (P<0.05) at14days, the expression of Ntcp had no significant differences (P>0.05) at7and14days, but significantly increased (P<0.05) at21days. After Yin-Zhi-Huang granules intervening for7,14and21days, compared with the same day's Saline group, no significant differences was observed in expression of Bsep (P>0.05), the expression of Mrp2had no significant differences (P>0.05) at14days, but significantly increased (P<0.05) at7and21days, the expression of Oatp2and Ntcp had no significant differences (P>0.05) at7days, but significantly increased (P<0.05) at14and21days.
Conclusion
The mechanism of Yin-Zhi-Huang granules on treatment of rat intrahepatic cholestasis induced by estrogen may be associated with the up-regulated expression of the hepatic transporter Oatp2, Ntcp and Mrp2. In addition, it may also relate with the body's compensatory mechanism on the up-regulated expression of Bsep.
探讨茵栀黄颗粒治疗雌激素诱导的大鼠胆汁淤积的作用机制。
方法
用苯甲酸雌二醇(EB,5mg/kg/d)颈部皮下连续注射5d,建立大鼠肝内胆汁淤积模型,对造模成功大鼠随即分为7组,1组为模型组,另6组分别用生理盐水和茵栀黄颗粒灌胃干预7、14、21d,此外,另设1正常对照组,通过胆汁流速、总胆汁流量、血清生化指标、肝脏病理学、免疫组化及Western-blot对各组大鼠进行评价对比。
结果
1.胆汁流速：用EB皮下注射5d后,模型组与正常对照组相比,胆汁流速及总胆汁流量均下降(P<0.05)。生理盐水分别干预7、14、21d时,其与模型组相比,其胆汁流速及总胆汁流量均呈现上升的趋势,但无显著差异。茵栀黄颗粒分别干预7、14、21d时,其与相同天数的生理盐水组相比,其胆汁流速与总胆汁流量均有上升趋势,其中以14、21d增加显著(P<0.05)。
2.血清生化指标：模型组与正常对照组相比,各项血清生化指标呈现上升的趋势,但以DBIL及TBA的升高最为显著(P<0.05)。生理盐水分别干预7、14、21d后,与模型组相比,7d其生化指标无差异(P>0.05)；14d其生化指标上升趋势明显,以DBIL及TBA的升高最为显著(P<0.05)；21d生化指标呈现下降趋势,以TBA下降最为显著(P<0.05)。茵栀黄颗粒分别干预7、14、21d后,与相同天数的生理盐水组相比,14d血清生化指标下降趋势明显,以DBIL及TBA的下降最为显著(P<0.05)；7和21d时无显著变化(P<0.05)
3.肝脏HE染色：正常对照组肝组织结构和细胞形态正常。模型组与正常对照组相比,肝组织出现少量胆管增生,静脉扩张淤血及局部肝细胞坏死变性,少量的炎症细胞浸润。生理盐水分别干预7、14、21d后,与模型组相比,7至14d肝脏病变呈持续加重趋势,21d呈缓解趋势。茵栀黄颗粒分别干预7、14、21d后,与相同天数的生理盐水组相比,其肝脏病变程度均减轻,21d已基本恢复正常。
4.免疫组化：各组大鼠肝脏转运体Mrp2,Oatp2,Bsep及Ntcp均表达于细胞膜上,未见内陷。
5. Western-blot:模型组与正常对照组相比,转运体Oatp2、Ntcp、Bsep及Mrp2表达均显著下降(P<0.05)。生理盐水组分别干预7、14、21d后与模型组相比,转运体Bsep及Mrp2的表达逐渐上升,其中14、21d出现显著性差异(P<0.05)；Oatp2的表达在7、21d时无显著变化(P>0.05),但14d时显著下降(P<0.05)；Ntcp的表达在7、14d时无显著变化(P>0.05),但21d时显著升高(P<0.05)。茵栀黄颗粒分别干预7、14、21d后与相同天数的生理盐水组相比,转运体Bsep的表达均无显著变化(P>0.05)；Mrp2的表达在14d时无显著变化(P>0.05),但7、21d时其表达均显著升高(P<0.05)；Oatp2及Ntcp的表达7d时均无显著变化(P>0.05),但14、21d时表达均显著升高(P<0.05)。
结论
茵栀黄颗粒治疗雌激素诱导大鼠肝内胆汁淤积的作用机制可能与其上调肝细胞膜转运体Oatp2、Ntcp及Mrp2的表达有关,此外,也可能与机体代偿性上调Bsep的表达有关。
Aim
Study on the treatment mechanism of Yin-Zhi-Huang granules to rat cholestasis induced by estrogen
Methods
Rat's intrahepatic cholestasis was induced by estradiol benzoate (EB,5mg/kg/d) via subcutaneous injection for5days, The successfully established experimental intrahepatic cholestasis rats models were randomly divided into7groups, one of them was Model group and other groups were interfered with saline and Yin-Zhi-Huang granules via oral administration for7,14and21days, respectively, no special treatment was required for the Normal group. Then rats were evaluated through comparing bile flow velocity, bile flow volume, biochemical indicator of blood serum, hepatic pathology, immunohistochemistry and western blot.
Results
1. Bile flow experiment: After having been given EB daily subcutaneous injection for5days, bile flow velocity and bile flow volume were decreased compared with Normal group (P<0.05). After saline intervening for7,14and21days, compared with Model group, bile flow velocity and bile flow volume were on the rise, but there was no significant difference. After Yin-Zhi-Huang granules intervening for7,14and21days, bile flow velocity and bile flow volume were on the rise and they were significantly increased (P<0.05) at14and21days compared with the same day's in Saline group.
2. Serum biochemical indexes:Compared with Normal group, serum biochemical indexes were on the rise in Model group, the direct bilirubin and total bile acid was significantly increased (P<0.05). After saline intervening for7,14and21days, compared with Model group, there was no significant difference in7days (P>0.05), serum biochemical indexes were on the rise in14days and the the direct bilirubin and total bile acid was significantly increased (P<0.05). It showed a downward tendency at21days and the total bile acid was significantly decreased (P<0.05). After Yin-Zhi-Huang granules intervening for7,14and21days, compared with the same day's Saline group, serum biochemical indexes had very marked drop trends, the the direct bilirubin and total bile acid were significantly decreased (P<0.05) at14days, there were no significant differences (P>0.05) at7and21days.
3. Liver HE staining: The hepatic tissue structure was normal in Normal group. After EB daily subcutaneous injection for5days, compared with Normal group, there were a small number of bile duct hyperplasia, venous congestion, partial hepatocytes necrosis, and inflammatory cell infiltration in rat liver. After saline intervening for7,14and21days, compared with Model group, the lesions showed a continuous aggravating trend from7to14days, it showed a remission trend at21days. After Yin-Zhi-Huang granules intervening for7,14and21days, the hepatic lesion was much more alleviative than the same day's Saline group, even recovered to normal at21days.
4. Immunohistochemistry showed that the transporter Mrp2, Oatp2, Bsep and Ntcp were all expressed in the liver cell membrane in each group, there was no internalization.
5. Western-blot experiment:Compared with Normal group, the expression of the hepatic Oatp2, Ntcp, Bsep and Mrp2were all significantly decreased (P<0.05). After saline intervening for7,14and21days, compared with Model group, the expression of the transporter Bsep and Mrp2were on the rise, and there was significantly difference at7and14days, the expression of Oatp2had no significant differences (P>0.05) at7and21days, but significantly decreased (P<0.05) at14days, the expression of Ntcp had no significant differences (P>0.05) at7and14days, but significantly increased (P<0.05) at21days. After Yin-Zhi-Huang granules intervening for7,14and21days, compared with the same day's Saline group, no significant differences was observed in expression of Bsep (P>0.05), the expression of Mrp2had no significant differences (P>0.05) at14days, but significantly increased (P<0.05) at7and21days, the expression of Oatp2and Ntcp had no significant differences (P>0.05) at7days, but significantly increased (P<0.05) at14and21days.
Conclusion
The mechanism of Yin-Zhi-Huang granules on treatment of rat intrahepatic cholestasis induced by estrogen may be associated with the up-regulated expression of the hepatic transporter Oatp2, Ntcp and Mrp2. In addition, it may also relate with the body's compensatory mechanism on the up-regulated expression of Bsep.
引文
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