清热祛湿法对胆汁淤积大鼠的作用及肝脏膜转运体Mrp2变化规律的研究
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摘要
胆汁淤积(cholestasis)是由多种原因所致的胆汁分泌或排泄障碍,导致胆汁不能正常流入十二指肠,从而反流入血液中。临床上常表现为黄疸,瘙痒,尿色深,粪色变浅或黄斑瘤等,实验室检查可有血清胆红素,碱性磷酸酶(ALP),5-核苷酸酶和γ-谷氨酰转移酶(GGT)水平升高,血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)提示有肝细胞损伤,慢性胆汁淤积常有总胆固醇水平升高。胆汁淤积( cholestasis)不是一种疾病,而是一组疾病共同的临床症状,故称为胆汁淤积综合征更为恰当。该综合征在临床上常见。随着对胆汁分泌和排泄的分子机制认识的不断深入,对胆汁淤积概念的理解也有了新的拓展。传统观念认为胆汁淤积是肝内、外梗阻因素造成胆汁形成后流动受阻,这种仅仅基于解剖学上的理解显然是不全面的。目前认为胆汁淤积是指胆汁生成障碍和(或)胆汁流动障碍。尽管对胆汁淤积性肝病分子机制的认识取得了一些进展,不同病因所致胆汁淤积的分子机制正逐步得以阐明,但胆汁淤积(尤其是肝内胆汁淤积)的治疗尚未获得根本性突破。如何从分子水平深入理解和开展胆汁淤积的药物治疗,仍是肝病学者面对的艰难课题。
目的:观察都具有清热祛湿功效的三个中药复方茵陈蒿汤、茵陈五苓散与大柴胡汤对胆汁淤积性肝纤维化大鼠的药理作用及肝脏膜转运体Mrp2变化规律的研究。
方法:采用肝外胆管结扎(BDL)和α-萘异硫氰酸酯(ANIT)灌胃方法诱导大鼠肝损伤,形成胆汁淤积性肝纤维化模型,以茵陈蒿汤、茵陈五苓散与大柴胡汤进行灌胃治疗,分别在造模后取四个时相点(BDL模型分别在造模后第3天,1周,2周,3周/ANIT模型于造模后第24,48,72,96小时)动态观测实验性大鼠一般情况,肝肾功能变化,肝组织病理学变化和纤维化程度以及三种中药方剂的干预的作用。
结果:
1.与假手术组比较,BDL模型组大鼠的体重都有不同程度的降低;肝重,脾重,肝指数,脾指数呈增高的动态变化;通过对造模后3天,1周,2周,3周的大鼠肝脏HE染色病理学形态观察和天狼星红胆染色对肝脏胶原纤维的观察,结扎3天后,汇管区已有胆管增生,至3周时增生逐渐加重;血清Alb含量持续下降;而GLO、TP含量先高后低的变化; TBil含量,GGT、ALP活性呈持续增高; ALT活性,TBA、CHE含量在造模3天后即显著增高,此后有所下降,至3周末仍高于假手术组(P<0.01,P<0.05),AST在3天后即显著增高并维持至3周末。LDH活性在造模1周时显著增高,即后有所下降;RUN含量在造模后前2周无明显改变,至第3周有所增高;CRE含量无统计学意义。
2.在BDL模型中,与模型组比较,所有用药干预组体重、肝重、肝/体重比值都有所降低,但统计学无意义,脾重、脾/体重比值显著降低(P<0.05);三个用药干预组胆管样上皮细胞或小胆管明显减少,肝细胞相对变多,胶原纤维增生减少,肝组织纤维化程度减轻,尤以茵陈蒿汤组疗效明显;茵陈蒿汤组ALB含量、LDH活性增加;各药物干预组TBil、TBA含量及ALP活性均降低;茵陈蒿汤组和茵陈五苓散组TBA含量、GGT活性显著降低(P<0.01)。
3.与正常组比较,ANIT模型组大鼠的体重都有不同程度的降低,,肝重,肝指数呈增高的动态变化,脾重,脾指数先增高后在造模72h时降低的动态变化;造模后24h汇管区就有胆管上皮细胞增生,少量炎性细胞浸润,72h时胆管上皮细胞增生范围增大,胶原纤维增生,96h增生的小胆管样上皮细胞开始缩小;Alb含量下降,96h接近正常水平;GLO、TP、CHE含量无明显变化; TBil、TBA含量,ALT、AST活性24h和72h时明显增高(P<0.05), 48h和96h接近正常;ALP、GGT显著增高(P<0.05),96h时接近正常;LDH活性显著下降(P<0.05),96h升高;RUN含量24h时下降,即后增高接近正常水平;CRE含量在48h,72h时增高(P<0.05),96h时恢复正常;肝组织Mrp2转运蛋白在正常组肝脏组织的Mrp2阳性表达量最多,在模型组24h、48h、72h的Mrp2的阳性表达量逐渐减少,在模型组96小时Mrp2的阳性表达量增多。
4.在ANIT模型中,所有用药干预组体重,肝重显著降低,茵陈蒿汤、大柴胡汤的肝/体重比值显著降低(P<0.05),茵陈五苓散的肝/体重比值,所有用药干预组脾重也有所降低,但无统计学意义;与模型组相比,三个用药干预组胆管样上皮细胞或小胆管明显减少,肝细胞相对变多,胶原纤维增生减少,肝组织纤维化程度减轻,尤以茵陈蒿汤组疗效明显;肝组织Mrp2转运蛋白在三个用药干预组都增多,尤其是茵陈蒿汤最明显(P<0.05)。
结论:
1.无论是BDL模型还是ANIT模型,胆汁淤积性大鼠肝纤维化模型主要病理改变有胆汁淤积、胆管上皮细胞增生、肝细胞减少、胶原增生和沉积,与新生的胆管上皮细胞关系密切。
2.进一步证实了理论上成立的胆汁淤积性疾病的发病机制与多药耐药相关蛋白2(Mrp2)的表达有关。
3.都具有清热祛湿功效的茵陈蒿汤,茵陈五苓散,大柴胡汤有较为显著的抗大鼠实验性肝纤维化的作用,且以茵陈蒿汤治疗效果最好,从试验结果来以方测证,胆汁淤积性疾病以热重于湿的证型为主。
Cholestasis is by many kinds of reason result choleresis or the excretion barrier, causes the bile not to be able to flow in the duodenum normally, thus the regurgitation enters in the blood. On clinical often the performance is the jaundice, the pruritus, urinates the color to be deep, the excrement color shoal or the xanthelasma and so on, the laboratory inspection may have TBil, ALP, 5- nucleotidases and GGT the level elevates, ALT and AST prompts has the liver cell damage, the chronic bile siltation common total cholesterol level elevates.
Objective:The observation has the refrigeration to dispel the wet effect three traditional Chinese medicine compound prescription Herbae Artemisiae Capillariae Decoction, Artenisiae Scopariae and Poriae Powder and tdaisaikoto to the bile siltation liver fibrosis big mouse's pharmacological action and the liver membrane transportation body Mrp2 change rule research.
Method:Uses outside the liver the bile duct ligation (BDL) and Alpha-naphthylisothiocyanate (ANIT) fills the stomach method to induce the big mouse liver damage, forms the bile siltation liver fibrosis model, by the Herbae Artemisiae Capillariae Decoction, Artenisiae Scopariae and Poriae Powder and tdaisaikoto carries on fills the stomach treatment, after making the mold separately takes four phase (the BDL model separately after making mold the 3rd day, the 1th week, the 2nd week, the 3rd week /ANIT model making mold the 24,48,72,96th hour) dynamic observation experimental nature big mouse ordinary circumstances, hepatorenal function change, liver organization pathology change and fibrosis degree as well as three formula medicinal preparation intervention function.
Result:
1.Compares with the sham-operation group, the BDL model group big mouse's body weight has varying degree reduction; Liver's weight, spleen's weight, the liver index, the spleen index assumes the markup the dynamic change; Through after making the mold the 3rd day, the 1st week, the 2nd week, the 3rd week-long big mouse liver HE dyeing pathology shape observation and the sirius red gallbladder dyes to the liver collagenous fibre observation, ties up 3 days later, collects the district to have the bile duct proliferation, to 3 weeks when the proliferation aggravates gradually; The blood serum Alb content drops continually; But GLO, TP content first elevation then reduction ; The TBil content, the GGT and ALP activeness assumes advances continually; The ALT activeness, the TBA and CHE content namely the remarkable markup makes the mold 3 days later, hereafter drops, to 3 weekend was still higher than the sham-operation group (P<0.01,P<0.05); AST 3 days later namely obviously advances and maintains to 3 weekends. The LDH activeness when makes the mold 1 week remarkable markup, after namely, drops; The RUN content after making the mold previous 2 weeks change not obviously, have the markup to the 3rd week; CRE content non-statistics significance.
2.In the BDL model, compares with the model group, all medication intervention group body weight, liver's weight, liver/body weight ratio have reduce, but statistics is insignificant, spleen's weight, the spleen/body weight ratio obviously reduce(P<0.05); In three medication intervention group bile duct type epithelial cell or the small bile duct obvious reduction, the liver cell changes many relatively, the collagenous fibre proliferation reduces, the liver organization fibrosis degree reduces, is especially obvious by theHerbae Artemisiae Capillariae Decoction group curative effect; The Herbae Artemisiae Capillariae Decoction group ALB content, the LDH activeness increase; Various medicines intervention group TBil, the TBA content and the ALP activeness reduce; The Herbae Artemisiae Capillariae Decoction group and the Artenisiae Scopariae and Poriae Powder group TBA content, the GGT activeness obviously to reduce(P<0.01).
3.Compares with the normal group, the ANIT model group big mouse's body weight has varying degree reduction, liver's weight, the liver index assumes the markup the dynamic change, spleen's weight, the spleen index advances first, the dynamic change which then when makes mold 72h reduces; After making the mold, 24h collects the district to have the bile duct epithelial cell proliferation, few inflammatory cell infiltration, when 72h the bile duct epithelial cell proliferation scope increases, the collagenous fibre proliferation, the 96h proliferation's small bile duct type epithelial cell starts to reduce; The Alb content drops, 96h close normal level; GLO, TP, the CHE content changes not obviously; TBil, TBA content, the ALT and AST active 24h and 72h obvious markup (P<0.05), 48h and 96h close normal; ALP, GGT remarkable markup P<0.05), when 96h close normal; The LDH activeness remarkable drop (P< 0.05), 96h elevates; When RUN content 24h drops, after namely, advances the close normal level; CRE content when 48h,72h advances (P<0.05), when 96h restores normally; The liver organizes the Mrp2 transportation protein the Mrp2 masculine gender expression quantity which organizes in the normal group liver to be most, in model group 24h, 48h, 72h Mrp2 masculine expression quantity reduces gradually, increases in the model group 96 hour Mrp2 masculine expression quantity.
4.In the ANIT model, all medication intervention group body weight, liver's weight obviously reduces, Herbae Artemisiae Capillariae Decoction, daisaikoto's liver/body weight ratio obviously reduces (P<0.05), the artemisia capillaris five water chestnuts disperse liver/body weight ratio, all medication intervention group spleen heavy also has reduces, but non-statistics significance; Compares with the model group, three medication intervention group bile duct type epithelial cell or the small bile duct obvious reduction, the liver cell changes many relatively, the collagenous fibre proliferation reduces, the liver organization fibrosis degree reduces, is especially obvious by the artemisia capillaris soup group curative effect; The liver organizes the Mrp2 transportation protein to increase in three medication intervention group, particularly the artemisia capillaris soup is most obvious (P<0.05).
Conclusion:
1.Regardless of being the BDL model or the ANIT model, the bile siltation big mouse liver fibrosis model main pathology change has the bile to silt up, the bile duct epithelial cell proliferation, the liver cell to reduce, the collagen proliferation and the deposition, is close with the newborn bile duct epithelial cell relations .
2.Further confirmed the bile siltation disease's pathogenesis which in the theory establishes bears the medicine related protein with the multi-medicines 2 (Mrp2) the expression related.
3.Has the refrigeration to dispel the wet effectHerbae Artemisiae Capillariae Decoction, Artenisiae Scopariae and Poriae Powder, daisaikoto has the more remarkable anti-big mouse experimental liver fibrosis function, and is best by Artemisiae Capillariae Decoction, Artenisiae Scopariae treatment result, comes from the test result by the formula to examine the card, bile siltation disease by Hot Preponderancy Wet card primarily.
目的:观察都具有清热祛湿功效的三个中药复方茵陈蒿汤、茵陈五苓散与大柴胡汤对胆汁淤积性肝纤维化大鼠的药理作用及肝脏膜转运体Mrp2变化规律的研究。
方法:采用肝外胆管结扎(BDL)和α-萘异硫氰酸酯(ANIT)灌胃方法诱导大鼠肝损伤,形成胆汁淤积性肝纤维化模型,以茵陈蒿汤、茵陈五苓散与大柴胡汤进行灌胃治疗,分别在造模后取四个时相点(BDL模型分别在造模后第3天,1周,2周,3周/ANIT模型于造模后第24,48,72,96小时)动态观测实验性大鼠一般情况,肝肾功能变化,肝组织病理学变化和纤维化程度以及三种中药方剂的干预的作用。
结果:
1.与假手术组比较,BDL模型组大鼠的体重都有不同程度的降低;肝重,脾重,肝指数,脾指数呈增高的动态变化;通过对造模后3天,1周,2周,3周的大鼠肝脏HE染色病理学形态观察和天狼星红胆染色对肝脏胶原纤维的观察,结扎3天后,汇管区已有胆管增生,至3周时增生逐渐加重;血清Alb含量持续下降;而GLO、TP含量先高后低的变化; TBil含量,GGT、ALP活性呈持续增高; ALT活性,TBA、CHE含量在造模3天后即显著增高,此后有所下降,至3周末仍高于假手术组(P<0.01,P<0.05),AST在3天后即显著增高并维持至3周末。LDH活性在造模1周时显著增高,即后有所下降;RUN含量在造模后前2周无明显改变,至第3周有所增高;CRE含量无统计学意义。
2.在BDL模型中,与模型组比较,所有用药干预组体重、肝重、肝/体重比值都有所降低,但统计学无意义,脾重、脾/体重比值显著降低(P<0.05);三个用药干预组胆管样上皮细胞或小胆管明显减少,肝细胞相对变多,胶原纤维增生减少,肝组织纤维化程度减轻,尤以茵陈蒿汤组疗效明显;茵陈蒿汤组ALB含量、LDH活性增加;各药物干预组TBil、TBA含量及ALP活性均降低;茵陈蒿汤组和茵陈五苓散组TBA含量、GGT活性显著降低(P<0.01)。
3.与正常组比较,ANIT模型组大鼠的体重都有不同程度的降低,,肝重,肝指数呈增高的动态变化,脾重,脾指数先增高后在造模72h时降低的动态变化;造模后24h汇管区就有胆管上皮细胞增生,少量炎性细胞浸润,72h时胆管上皮细胞增生范围增大,胶原纤维增生,96h增生的小胆管样上皮细胞开始缩小;Alb含量下降,96h接近正常水平;GLO、TP、CHE含量无明显变化; TBil、TBA含量,ALT、AST活性24h和72h时明显增高(P<0.05), 48h和96h接近正常;ALP、GGT显著增高(P<0.05),96h时接近正常;LDH活性显著下降(P<0.05),96h升高;RUN含量24h时下降,即后增高接近正常水平;CRE含量在48h,72h时增高(P<0.05),96h时恢复正常;肝组织Mrp2转运蛋白在正常组肝脏组织的Mrp2阳性表达量最多,在模型组24h、48h、72h的Mrp2的阳性表达量逐渐减少,在模型组96小时Mrp2的阳性表达量增多。
4.在ANIT模型中,所有用药干预组体重,肝重显著降低,茵陈蒿汤、大柴胡汤的肝/体重比值显著降低(P<0.05),茵陈五苓散的肝/体重比值,所有用药干预组脾重也有所降低,但无统计学意义;与模型组相比,三个用药干预组胆管样上皮细胞或小胆管明显减少,肝细胞相对变多,胶原纤维增生减少,肝组织纤维化程度减轻,尤以茵陈蒿汤组疗效明显;肝组织Mrp2转运蛋白在三个用药干预组都增多,尤其是茵陈蒿汤最明显(P<0.05)。
结论:
1.无论是BDL模型还是ANIT模型,胆汁淤积性大鼠肝纤维化模型主要病理改变有胆汁淤积、胆管上皮细胞增生、肝细胞减少、胶原增生和沉积,与新生的胆管上皮细胞关系密切。
2.进一步证实了理论上成立的胆汁淤积性疾病的发病机制与多药耐药相关蛋白2(Mrp2)的表达有关。
3.都具有清热祛湿功效的茵陈蒿汤,茵陈五苓散,大柴胡汤有较为显著的抗大鼠实验性肝纤维化的作用,且以茵陈蒿汤治疗效果最好,从试验结果来以方测证,胆汁淤积性疾病以热重于湿的证型为主。
Cholestasis is by many kinds of reason result choleresis or the excretion barrier, causes the bile not to be able to flow in the duodenum normally, thus the regurgitation enters in the blood. On clinical often the performance is the jaundice, the pruritus, urinates the color to be deep, the excrement color shoal or the xanthelasma and so on, the laboratory inspection may have TBil, ALP, 5- nucleotidases and GGT the level elevates, ALT and AST prompts has the liver cell damage, the chronic bile siltation common total cholesterol level elevates.
Objective:The observation has the refrigeration to dispel the wet effect three traditional Chinese medicine compound prescription Herbae Artemisiae Capillariae Decoction, Artenisiae Scopariae and Poriae Powder and tdaisaikoto to the bile siltation liver fibrosis big mouse's pharmacological action and the liver membrane transportation body Mrp2 change rule research.
Method:Uses outside the liver the bile duct ligation (BDL) and Alpha-naphthylisothiocyanate (ANIT) fills the stomach method to induce the big mouse liver damage, forms the bile siltation liver fibrosis model, by the Herbae Artemisiae Capillariae Decoction, Artenisiae Scopariae and Poriae Powder and tdaisaikoto carries on fills the stomach treatment, after making the mold separately takes four phase (the BDL model separately after making mold the 3rd day, the 1th week, the 2nd week, the 3rd week /ANIT model making mold the 24,48,72,96th hour) dynamic observation experimental nature big mouse ordinary circumstances, hepatorenal function change, liver organization pathology change and fibrosis degree as well as three formula medicinal preparation intervention function.
Result:
1.Compares with the sham-operation group, the BDL model group big mouse's body weight has varying degree reduction; Liver's weight, spleen's weight, the liver index, the spleen index assumes the markup the dynamic change; Through after making the mold the 3rd day, the 1st week, the 2nd week, the 3rd week-long big mouse liver HE dyeing pathology shape observation and the sirius red gallbladder dyes to the liver collagenous fibre observation, ties up 3 days later, collects the district to have the bile duct proliferation, to 3 weeks when the proliferation aggravates gradually; The blood serum Alb content drops continually; But GLO, TP content first elevation then reduction ; The TBil content, the GGT and ALP activeness assumes advances continually; The ALT activeness, the TBA and CHE content namely the remarkable markup makes the mold 3 days later, hereafter drops, to 3 weekend was still higher than the sham-operation group (P<0.01,P<0.05); AST 3 days later namely obviously advances and maintains to 3 weekends. The LDH activeness when makes the mold 1 week remarkable markup, after namely, drops; The RUN content after making the mold previous 2 weeks change not obviously, have the markup to the 3rd week; CRE content non-statistics significance.
2.In the BDL model, compares with the model group, all medication intervention group body weight, liver's weight, liver/body weight ratio have reduce, but statistics is insignificant, spleen's weight, the spleen/body weight ratio obviously reduce(P<0.05); In three medication intervention group bile duct type epithelial cell or the small bile duct obvious reduction, the liver cell changes many relatively, the collagenous fibre proliferation reduces, the liver organization fibrosis degree reduces, is especially obvious by theHerbae Artemisiae Capillariae Decoction group curative effect; The Herbae Artemisiae Capillariae Decoction group ALB content, the LDH activeness increase; Various medicines intervention group TBil, the TBA content and the ALP activeness reduce; The Herbae Artemisiae Capillariae Decoction group and the Artenisiae Scopariae and Poriae Powder group TBA content, the GGT activeness obviously to reduce(P<0.01).
3.Compares with the normal group, the ANIT model group big mouse's body weight has varying degree reduction, liver's weight, the liver index assumes the markup the dynamic change, spleen's weight, the spleen index advances first, the dynamic change which then when makes mold 72h reduces; After making the mold, 24h collects the district to have the bile duct epithelial cell proliferation, few inflammatory cell infiltration, when 72h the bile duct epithelial cell proliferation scope increases, the collagenous fibre proliferation, the 96h proliferation's small bile duct type epithelial cell starts to reduce; The Alb content drops, 96h close normal level; GLO, TP, the CHE content changes not obviously; TBil, TBA content, the ALT and AST active 24h and 72h obvious markup (P<0.05), 48h and 96h close normal; ALP, GGT remarkable markup P<0.05), when 96h close normal; The LDH activeness remarkable drop (P< 0.05), 96h elevates; When RUN content 24h drops, after namely, advances the close normal level; CRE content when 48h,72h advances (P<0.05), when 96h restores normally; The liver organizes the Mrp2 transportation protein the Mrp2 masculine gender expression quantity which organizes in the normal group liver to be most, in model group 24h, 48h, 72h Mrp2 masculine expression quantity reduces gradually, increases in the model group 96 hour Mrp2 masculine expression quantity.
4.In the ANIT model, all medication intervention group body weight, liver's weight obviously reduces, Herbae Artemisiae Capillariae Decoction, daisaikoto's liver/body weight ratio obviously reduces (P<0.05), the artemisia capillaris five water chestnuts disperse liver/body weight ratio, all medication intervention group spleen heavy also has reduces, but non-statistics significance; Compares with the model group, three medication intervention group bile duct type epithelial cell or the small bile duct obvious reduction, the liver cell changes many relatively, the collagenous fibre proliferation reduces, the liver organization fibrosis degree reduces, is especially obvious by the artemisia capillaris soup group curative effect; The liver organizes the Mrp2 transportation protein to increase in three medication intervention group, particularly the artemisia capillaris soup is most obvious (P<0.05).
Conclusion:
1.Regardless of being the BDL model or the ANIT model, the bile siltation big mouse liver fibrosis model main pathology change has the bile to silt up, the bile duct epithelial cell proliferation, the liver cell to reduce, the collagen proliferation and the deposition, is close with the newborn bile duct epithelial cell relations .
2.Further confirmed the bile siltation disease's pathogenesis which in the theory establishes bears the medicine related protein with the multi-medicines 2 (Mrp2) the expression related.
3.Has the refrigeration to dispel the wet effectHerbae Artemisiae Capillariae Decoction, Artenisiae Scopariae and Poriae Powder, daisaikoto has the more remarkable anti-big mouse experimental liver fibrosis function, and is best by Artemisiae Capillariae Decoction, Artenisiae Scopariae treatment result, comes from the test result by the formula to examine the card, bile siltation disease by Hot Preponderancy Wet card primarily.
引文
[1] Gall JAM ,Bhathal PS , A quantitative analysis of the liver following ligation of common bile duct .Liver ,1990 ,10 :116～125
[2]沈宏亮,徐冠南,陈克明等1IFNγ防治大鼠胆总管结扎所致肝纤维化的实验研究.第二军医大学学报,1999 ,20 (1) :48
[3]尹珊珊,王宝恩,王泰龄,等.胆管阻塞性肝纤维化模型的建立与改进.中华肝脏病杂志;2002 ,10 (5) :385～386.
[4]刘钺,张朝明,郝玲,等.血清总胆红素、甘氨胆酸、甲胎蛋白、糖类抗原19-9与胆汁淤滞相关性评价.国际放射医学核医学杂志,2006,30(2):107～109
[5]姚光弼,范上达,廖家杰.临床肝脏病学.上海:上海科学技术出版社,2004
[6]龙爱华,刘平,李风华等.不同配比黄芪汤干预大鼠胆汁淤积性肝硬化作用观察.中国实验方剂学杂志.2006,12(7):28～30
[1] JAM,Bhathal PS, A quantitative analysis of the liver following ligation of common bile duct. Liver,1990,10:116-125
[2]沈宏亮,徐冠南,陈克明,等.IFNγ防治大鼠胆总管结扎所致肝纤维化的实验研究.第二军医大学学报,1999,20(1):48
[3]陆伦根.胆汁淤积的发生机制和诊治策略.胃肠病学,2005,10(3):188
[4]龙爱华,刘平,李风华,等.不同配比黄芪汤干预大鼠胆汁淤积性肝硬化作用观察.中国实验方剂学杂志,2006,12(7):28
[1]沈宏亮,徐冠南,陈克明等1IFNγ防治大鼠胆总管结扎所致肝纤维化的实验研究.第二军医大学学报,1999 ,20 (1) :48
[2] Kossor DC, Meunier PC, Handler JA, Sozio RS, Goldstein RS. Temporal relation-ship of changes in hepatobiliary function and morphology in rats following alpha-naphthylisothiocyanate (ANIT) administration. Toxicol Appl Pharmacol 1993; 119: 108-114
[1] Kullak Ublick GA,BeuersU,Paumgartner G. Hepatobiliary transport.J Hepatol, 2000,32:3-18.
[2] Vos TA,Hooiveld GJ,KoningH,et al. Up2regulation of the multidrug resistance genes,MRP1 and Mdr1b,and down2regulation of the organic anion transporter,MRP2, and the bile salt transporter, Spgp, in endotoxemic rat liver. Hepatology,1998,28:1637-1644.
[3] Tanaka Y, Kobayashi Y, Gabazza E C, et al. Increased renal exp ression of bilirubin glucuronide transporters in a rat model of obstructive jaundice. Am J Physiol GastrointestLiver Physiol,2002,282:G656-G662.
[4] Kepp lerD, Konig J. Hepatic secretion of conjugated drugs and endogenous substances. Semin LiverDis,2000,20:265-272.
[5]姚光弼,范上达,廖家杰.临床肝脏病学.上海:上海科学技术出版社,2004
[6] Tsujii H, Konig J, Rost D, et al. Exon2intron organization of the human multidrug resistance protein 2 (MRP2) gene mutated in DubinJohnson syndrome. Gastroenterology, 1999,117:653-660.
[7] StockelB, Konig J, NiesA T, et al. Characterization of the 5’2flanking region of the human multidrug resistance p rotein 2 (MRP2) gene and its regulation in comparison with the multidrug resistance protein 3(MRP3) gene. Eur J Biochem,2000,267:1347-1358.
[8] Cherrington N J, HartleyD P, LiN, et al. Organ distribution ofmultidrug resistance proteins 1,2,and 3 (MRP1,2,and 3) mRNA and hepatic induction of MRP3 by constitutive androstane receptor activators in rats. J Pharmacol Exp Ther, 2002,300:97-104
[9]陈应果,别平,祝建勇.胆红素主要转运子MRP2在大鼠梗阻性黄疸肝脏中的表达及意义。第三军医大学学报, 2004, 26: 1429-1431.
[10]吴晓飞,孔凡明,田雨等;胆囊胆固醇结石患者肝细胞MRP2基因表达的半定量研究。中华普通外科杂志,2004,19:375-376
[11]Scheffer G L, KoolM, de HaasM, et al. Tissue distribution and in 2 duction of human multidrug resistant protein 3.Lab Invest,2002, 82: 193 - 201.
[12] Hirohashi T, Suzuki H, Takikawa H, et al. ATP2dependent transport of bile salts by rat multidrug resistance2associated protein 3 (MRP3). J Biol Chem, 2000, 275: 2905 - 2910.
[13]Tanaka Y, Kobayashi Y, Gabazza E C, et al. Increased renal exp res2sion of bilirubin glucuronide transporters in a rat model of obstructivejaundice. Am J Physiol GastrointestLiver Physiol, 2002, 282:G656 - G662.
[14]李琼,陈文生,罗东林等;阻塞性胆汁淤积大鼠肝细胞膜蛋白MRP3与核受体RXRα蛋白表达关系的研究。第三军医大学学报, 2006, 28:1298-1301
[15] BOHAN A, CHEN W S, DENSON L A, et al. Tumor necrosis factoralpha-dependent up-regulation of Lrh21 and Mrp3 (Abcc3) reduces liver injury in obstructive cholestasis. J Biol Chem, 2003, 278:36688 - 36698.
[2]沈宏亮,徐冠南,陈克明等1IFNγ防治大鼠胆总管结扎所致肝纤维化的实验研究.第二军医大学学报,1999 ,20 (1) :48
[3]尹珊珊,王宝恩,王泰龄,等.胆管阻塞性肝纤维化模型的建立与改进.中华肝脏病杂志;2002 ,10 (5) :385～386.
[4]刘钺,张朝明,郝玲,等.血清总胆红素、甘氨胆酸、甲胎蛋白、糖类抗原19-9与胆汁淤滞相关性评价.国际放射医学核医学杂志,2006,30(2):107～109
[5]姚光弼,范上达,廖家杰.临床肝脏病学.上海:上海科学技术出版社,2004
[6]龙爱华,刘平,李风华等.不同配比黄芪汤干预大鼠胆汁淤积性肝硬化作用观察.中国实验方剂学杂志.2006,12(7):28～30
[1] JAM,Bhathal PS, A quantitative analysis of the liver following ligation of common bile duct. Liver,1990,10:116-125
[2]沈宏亮,徐冠南,陈克明,等.IFNγ防治大鼠胆总管结扎所致肝纤维化的实验研究.第二军医大学学报,1999,20(1):48
[3]陆伦根.胆汁淤积的发生机制和诊治策略.胃肠病学,2005,10(3):188
[4]龙爱华,刘平,李风华,等.不同配比黄芪汤干预大鼠胆汁淤积性肝硬化作用观察.中国实验方剂学杂志,2006,12(7):28
[1]沈宏亮,徐冠南,陈克明等1IFNγ防治大鼠胆总管结扎所致肝纤维化的实验研究.第二军医大学学报,1999 ,20 (1) :48
[2] Kossor DC, Meunier PC, Handler JA, Sozio RS, Goldstein RS. Temporal relation-ship of changes in hepatobiliary function and morphology in rats following alpha-naphthylisothiocyanate (ANIT) administration. Toxicol Appl Pharmacol 1993; 119: 108-114
[1] Kullak Ublick GA,BeuersU,Paumgartner G. Hepatobiliary transport.J Hepatol, 2000,32:3-18.
[2] Vos TA,Hooiveld GJ,KoningH,et al. Up2regulation of the multidrug resistance genes,MRP1 and Mdr1b,and down2regulation of the organic anion transporter,MRP2, and the bile salt transporter, Spgp, in endotoxemic rat liver. Hepatology,1998,28:1637-1644.
[3] Tanaka Y, Kobayashi Y, Gabazza E C, et al. Increased renal exp ression of bilirubin glucuronide transporters in a rat model of obstructive jaundice. Am J Physiol GastrointestLiver Physiol,2002,282:G656-G662.
[4] Kepp lerD, Konig J. Hepatic secretion of conjugated drugs and endogenous substances. Semin LiverDis,2000,20:265-272.
[5]姚光弼,范上达,廖家杰.临床肝脏病学.上海:上海科学技术出版社,2004
[6] Tsujii H, Konig J, Rost D, et al. Exon2intron organization of the human multidrug resistance protein 2 (MRP2) gene mutated in DubinJohnson syndrome. Gastroenterology, 1999,117:653-660.
[7] StockelB, Konig J, NiesA T, et al. Characterization of the 5’2flanking region of the human multidrug resistance p rotein 2 (MRP2) gene and its regulation in comparison with the multidrug resistance protein 3(MRP3) gene. Eur J Biochem,2000,267:1347-1358.
[8] Cherrington N J, HartleyD P, LiN, et al. Organ distribution ofmultidrug resistance proteins 1,2,and 3 (MRP1,2,and 3) mRNA and hepatic induction of MRP3 by constitutive androstane receptor activators in rats. J Pharmacol Exp Ther, 2002,300:97-104
[9]陈应果,别平,祝建勇.胆红素主要转运子MRP2在大鼠梗阻性黄疸肝脏中的表达及意义。第三军医大学学报, 2004, 26: 1429-1431.
[10]吴晓飞,孔凡明,田雨等;胆囊胆固醇结石患者肝细胞MRP2基因表达的半定量研究。中华普通外科杂志,2004,19:375-376
[11]Scheffer G L, KoolM, de HaasM, et al. Tissue distribution and in 2 duction of human multidrug resistant protein 3.Lab Invest,2002, 82: 193 - 201.
[12] Hirohashi T, Suzuki H, Takikawa H, et al. ATP2dependent transport of bile salts by rat multidrug resistance2associated protein 3 (MRP3). J Biol Chem, 2000, 275: 2905 - 2910.
[13]Tanaka Y, Kobayashi Y, Gabazza E C, et al. Increased renal exp res2sion of bilirubin glucuronide transporters in a rat model of obstructivejaundice. Am J Physiol GastrointestLiver Physiol, 2002, 282:G656 - G662.
[14]李琼,陈文生,罗东林等;阻塞性胆汁淤积大鼠肝细胞膜蛋白MRP3与核受体RXRα蛋白表达关系的研究。第三军医大学学报, 2006, 28:1298-1301
[15] BOHAN A, CHEN W S, DENSON L A, et al. Tumor necrosis factoralpha-dependent up-regulation of Lrh21 and Mrp3 (Abcc3) reduces liver injury in obstructive cholestasis. J Biol Chem, 2003, 278:36688 - 36698.
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