熊去氧胆酸联合地塞米松对大鼠妊娠期肝内胆汁淤积症的治疗作用
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摘要
目的探讨熊去氧胆酸联合地塞米松治疗大鼠妊娠期肝内胆汁淤积症(ICP)的效果。方法选取妊娠第10天Sprague Dawley大鼠给予孕激素诱导建立ICP模型,将造模成功的30只孕鼠随机分为联合治疗组和对照组,每组15只。妊娠第15～19天,2组孕鼠均每日给予熊去氧胆酸溶液灌胃(100 mg·kg~(-1)),共5 d;在此基础上,联合治疗组孕鼠每日肌肉注射地塞米松(1 mg·kg~(-1)),共5 d。分别于治疗前后检测2组大鼠血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、总胆酸(TBA)和总胆红素(TBIL)水平;测2组胎鼠体质量并计算死胎率;苏木精-伊红染色观察孕鼠肝脏病理学变化。结果治疗前2组孕鼠血清ALT、AST、TAB及TBIL水平比较差异均无统计学意义(P> 0. 05)。2组孕鼠治疗后血清ALT、AST、TAB及TBIL水平均低于治疗前(P <0. 05);治疗后,联合治疗组孕鼠血清ALT、AST、TAB及TBIL水平均低于对照组(P <0. 05)。联合治疗组和对照组胎鼠体质量分别为(4. 89±0. 53)、(4. 01±0. 33) g,死胎率分别为10. 1%(13/129)、14. 5%(18/124);联合治疗组胎鼠体质量高于对照组(t=12. 83,P <0. 05),死胎率低于对照组(χ~2=7. 81,P <0. 05)。对照组孕鼠肝细胞水肿明显,细胞质疏松,大量细胞脂肪变性,点状坏死较多,肝血窦变窄,胆管扩张且有胆汁淤积;联合治疗组孕鼠部分肝细胞水肿,少量细胞出现脂肪变性,毛细胆管扩张及部分炎性细胞浸润。结论地塞米松联合熊去氧胆酸可降低ICP孕鼠肝酶、总胆汁酸水平,保护孕鼠肝细胞,改善妊娠结局。
Objective To explore the effect of ursodeoxycholic acid combined with dexamethasone in the treatment of intrahepatic cholestasis of pregnancy( ICP) of rats. Methods The ICP model was established in Sprague Dawley rats on the tenth day of gestation by giving progesterone. Thirty ICP rats were randomly divided into control group and combined treatment group,with 15 rats in each group. On the 15 th-19 thday,all rats were given ursodeoxycholic acid solution( 100 mg·kg~(-1)) by intragastric administration for 5 days; based on this,the rats in the combined treatment group were intramuscularly injected with dexamethasone( 1 mg·kg~(-1)) for 5 days. The serum levels of alanine transarninase( ALT),aspartate aminotransferase( AST),total bile acid( TBA) and total bilirubin( TBIL) of rats in the two groups were detected before and after treatment. The body weight of fetal rats were measured and the still birth rate was calculated. The pathological changes of liver of pregnant rats were observed by hematoxylin eosin staining. Results There was no statistic difference in the serum levels of ALT,AST,TBA and TBIL of rats between the two groups before treatment( P > 0. 05). After treatment,the serum levels of ALT,AST,TBA and TBIL of rats in the two groups were significantly lower than those before treatment( P < 0. 05); and the serum levels of ALT,AST,TBA and TBIL of rats in the combined treatment group were significantly lower than those in the control group( P <0. 05). The body weight of fetal rats in the combined treatment group and control group was( 4. 89 ± 0. 53) g and( 4. 14 ±0. 33) g respectively,the still birth rate of fetal rat in the above two groups was 10. 1( 13/129) and 14. 5( 18/124)respectively; the body weight of fetal rats in the combined treatment group was higher than that in the control group( t = 12. 83,P < 0. 05),and the still birth rate of fetal rats in the combined treatment group was lower than that in the control group( χ~2=7. 81,P < 0. 05). The pathological changes of hepatic tissues of rats in the control group included the hepatocellular edema,loose cytoplasm,much cellular steatosis,more spotty necrosis,hepatic sinusoid narrowing,bile duct dilatation and cholestasis.The pathological changes of hepatic tissues of rats in the combined treatment group included some hepatocellular edema,a few cellular steatosis,cholangiectasis and inflammatory cell infiltrate. Conclusion The dexamethasone combined with ursodeoxycholic acid can reduce the levels of liver enzymes and TBA in ICP rats,protect the hepatocytes of pregnant rats and improve the prognosis of pregnancy.
Objective To explore the effect of ursodeoxycholic acid combined with dexamethasone in the treatment of intrahepatic cholestasis of pregnancy( ICP) of rats. Methods The ICP model was established in Sprague Dawley rats on the tenth day of gestation by giving progesterone. Thirty ICP rats were randomly divided into control group and combined treatment group,with 15 rats in each group. On the 15 th-19 thday,all rats were given ursodeoxycholic acid solution( 100 mg·kg~(-1)) by intragastric administration for 5 days; based on this,the rats in the combined treatment group were intramuscularly injected with dexamethasone( 1 mg·kg~(-1)) for 5 days. The serum levels of alanine transarninase( ALT),aspartate aminotransferase( AST),total bile acid( TBA) and total bilirubin( TBIL) of rats in the two groups were detected before and after treatment. The body weight of fetal rats were measured and the still birth rate was calculated. The pathological changes of liver of pregnant rats were observed by hematoxylin eosin staining. Results There was no statistic difference in the serum levels of ALT,AST,TBA and TBIL of rats between the two groups before treatment( P > 0. 05). After treatment,the serum levels of ALT,AST,TBA and TBIL of rats in the two groups were significantly lower than those before treatment( P < 0. 05); and the serum levels of ALT,AST,TBA and TBIL of rats in the combined treatment group were significantly lower than those in the control group( P <0. 05). The body weight of fetal rats in the combined treatment group and control group was( 4. 89 ± 0. 53) g and( 4. 14 ±0. 33) g respectively,the still birth rate of fetal rat in the above two groups was 10. 1( 13/129) and 14. 5( 18/124)respectively; the body weight of fetal rats in the combined treatment group was higher than that in the control group( t = 12. 83,P < 0. 05),and the still birth rate of fetal rats in the combined treatment group was lower than that in the control group( χ~2=7. 81,P < 0. 05). The pathological changes of hepatic tissues of rats in the control group included the hepatocellular edema,loose cytoplasm,much cellular steatosis,more spotty necrosis,hepatic sinusoid narrowing,bile duct dilatation and cholestasis.The pathological changes of hepatic tissues of rats in the combined treatment group included some hepatocellular edema,a few cellular steatosis,cholangiectasis and inflammatory cell infiltrate. Conclusion The dexamethasone combined with ursodeoxycholic acid can reduce the levels of liver enzymes and TBA in ICP rats,protect the hepatocytes of pregnant rats and improve the prognosis of pregnancy.
引文
[1]张雅琴,沈玲珑.餐后2小时血清甘胆酸测定对妊娠期肝内胆汁淤积症的早期诊断意义[J].中华全科医学,2015,13(4):36-37.(下转第32页)
[2]王利霞,韩利伟,魏丹丹.茵栀黄颗粒对妊娠期肝内胆汁淤积症糖脂代谢及胆盐载体的影响[J].世界中医药,2018,13(8):1871-1874.
[3]廖志,张勇,罗红权,等.妊娠期肝内胆汁淤积症孕妇所产新生儿脐动脉血清诱导A549细胞凋亡的机制研究[J].中华实用儿科临床杂志,2014,29(2):98-100.
[4]ABU-HAYYEH S,PAPACLEOVOULOU G,LOVGREN-SANDBLOMA,et al.Intrahpeatic cholestasis of pregnancylevels of sulfated progesterone metabolites inhibit farnesoid X receptorre-sulting ih a cholestatic phenotype[J].Hepatology,2013,57(2):716-726.
[5]周婷婷,王慧,南燕,等.雌激素、孕激素及雌激素联合孕激素诱导中孕期大鼠胆汁淤积症模型的比较[J].新乡医学院学报,2017,34(5):369-373.
[6]徐英芳,杜洁.熊去氧胆酸胶囊治疗正常肝内胆汁淤积症患者的疗效及对妊娠结局的影响[J].中国妇幼保健,2017,32(8):1646-1649.
[7]喻玲,赵莹,丁依玲.地塞米松对乙炔雌二醇诱发的肝内胆汁淤积症孕鼠儿茶酚氧位甲基转移酶活性、胎盘和肝脏组织雌激素受体表达的影响[J].国际病理科学与临床杂志,2010,30(4):282-283.
[8]郑金萍,赵英,张伯鹏.异甘草酸镁联合熊去氧胆酸治疗原发性胆汁性肝硬化的临床研究[J].世界中医药,2017,12(2):289-292.
[9]中华医学会妇产科学分会产科学组.妊娠期肝内胆汁淤积症诊疗指南[J].中华妇产科杂志,2015,50(7):481-485.
[10]周婷婷,王慧,祝燕莉,等.不同胆汁酸水平对妊娠期肝内胆汁淤积症孕妇和胎儿的影响[J].现代诊断与治疗,2017,28(11):2026-2027.
[11]周婷婷.地塞米松治疗孕鼠肝内胆汁淤积症中的调控机制探讨[D].新乡:新乡医学院,2017.
[2]王利霞,韩利伟,魏丹丹.茵栀黄颗粒对妊娠期肝内胆汁淤积症糖脂代谢及胆盐载体的影响[J].世界中医药,2018,13(8):1871-1874.
[3]廖志,张勇,罗红权,等.妊娠期肝内胆汁淤积症孕妇所产新生儿脐动脉血清诱导A549细胞凋亡的机制研究[J].中华实用儿科临床杂志,2014,29(2):98-100.
[4]ABU-HAYYEH S,PAPACLEOVOULOU G,LOVGREN-SANDBLOMA,et al.Intrahpeatic cholestasis of pregnancylevels of sulfated progesterone metabolites inhibit farnesoid X receptorre-sulting ih a cholestatic phenotype[J].Hepatology,2013,57(2):716-726.
[5]周婷婷,王慧,南燕,等.雌激素、孕激素及雌激素联合孕激素诱导中孕期大鼠胆汁淤积症模型的比较[J].新乡医学院学报,2017,34(5):369-373.
[6]徐英芳,杜洁.熊去氧胆酸胶囊治疗正常肝内胆汁淤积症患者的疗效及对妊娠结局的影响[J].中国妇幼保健,2017,32(8):1646-1649.
[7]喻玲,赵莹,丁依玲.地塞米松对乙炔雌二醇诱发的肝内胆汁淤积症孕鼠儿茶酚氧位甲基转移酶活性、胎盘和肝脏组织雌激素受体表达的影响[J].国际病理科学与临床杂志,2010,30(4):282-283.
[8]郑金萍,赵英,张伯鹏.异甘草酸镁联合熊去氧胆酸治疗原发性胆汁性肝硬化的临床研究[J].世界中医药,2017,12(2):289-292.
[9]中华医学会妇产科学分会产科学组.妊娠期肝内胆汁淤积症诊疗指南[J].中华妇产科杂志,2015,50(7):481-485.
[10]周婷婷,王慧,祝燕莉,等.不同胆汁酸水平对妊娠期肝内胆汁淤积症孕妇和胎儿的影响[J].现代诊断与治疗,2017,28(11):2026-2027.
[11]周婷婷.地塞米松治疗孕鼠肝内胆汁淤积症中的调控机制探讨[D].新乡:新乡医学院,2017.