移植肝“毒性胆汁”形成及导致胆管损伤机制的实验研究
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摘要
一、背景
胆道并发症严重影响肝移植受者的生存及生活质量,被公认为肝脏移植的薄弱环节(Achilles’heel)。随着人们对胆道并发症认识的深化和外科吻合技术的提高,由外科技术原因造成的胆管吻合口并发症及引流管相关性并发症的发病率呈下降的趋势,而以非外科技术因素所导致的以移植物胆管树损害为主要特征的供体胆管并发症则成为术后胆道并发症的主要类型,发生率为2%-19%。以弥漫性或局灶性的移植物胆管树狭窄、扩张、毁损及管型形成为病理特征的缺血性胆管病变(ITBL)被认为是非外科性移植物胆管树损害的主要原因。尽管公认冷保存/再灌注损伤(CPRI)是其发病的主要因素,但具体机制尚不清楚。近年来,疏水性胆盐在胆道损伤中的作用受到人们的重视。疏水性胆盐既可以通过“去垢”(detergent)作用干扰生物膜的脂代谢,也可以诱导细胞调亡,具有很强的细胞毒性。人的胆盐池95%以上由疏水性胆盐组成。正常情况下,人类具有一套中和疏水性胆盐细胞毒性的自我保护机制,如磷脂可以与胆盐形成微胶粒(micelle)以降低其细胞毒性、胆汁所含的亲水性胆盐可以通过增强细胞膜的稳定性来对抗疏水性胆盐的细胞毒性等等。此外,胆汁主要成分的分泌完全依赖于位于肝细胞毛细胆管面的肝胆膜转运蛋白(HMTs),HMTs基因表达异常有可能导致胆汁淤积和胆管损伤。已经有研究提示肝移植术后早期存在胆汁成分失衡的现象。综合近年来国内外的研究结果,我们提出了移植肝冷保存/再灌注胆管损伤的“毒性胆汁”假说:在经历CPRI后,移植肝HMTs及相关调控因子的表达及功能可能出现改变,导致机体对抗疏水性胆盐毒性的保护性机制被破坏,形成具有较强细胞毒性的“毒性胆汁”,最终对胆管造成损伤。显然,如果我们能对该假说加以验证,必将加深对移植肝胆道并发症发生机制的认识,也有助于拓展新的预防和治疗策略。
二、目的
疏水性胆盐具有很强的细胞毒性,在胆管损伤中扮演着重要角色。本研究拟以验证“毒性胆汁”假说为主要目的,建立一种适于移植肝胆道问题研究的大鼠肝移植模型,探讨经历CPRI后移植肝胆汁主要成分的变化规律及与胆管损伤的相关性,并对
Background
Biliary complications after orthotopic liver transplantation(OLT) have been a common problem since early beginning of this technique, which have been called“the Achilles’heel”of OLT by Sir Roy Calne. With the improvement of surgical techniques, the incidence rate of the biliary complications associated with bile duct anastomosis decreased remarkably, while the nonanastomotic stricture and dilatation involving only the biliary tree of the graft with a radiological appearance of biliary ischemia(Ischemic-type biliary lesions, ITBL) become the major type of biliary complications after OLT, which has be reported to occur at a relatively constant rate 15-26%. It is well known that the cold preservation-reperfusion injury(CPRI) plays an important role in the pathegenesis of ITBL.However, the details still remain unclear despite numerous studies. Recently, it is reported that hydrophobic bile salts play a role in the pathogenesis of bile duct injury. The hydrophobic bile salts are cytotoxic due to their potent detergent properities toward cellular membranes. Under normal circumstances, some protective mechanisms can prevent the cytotoxcity of bile salts. For instance, bile salts can be neutralized in the bile by complex formation with phospholipid and some hydrophilic bile salts can stabilize cell membranes. In addition, various selective transporter proteins in the sinusoidal and canalicular membrane of hepatocytes(hepatobiliary membrane transporters, HMTs) have been identified and were shown to play a role in the secretion of sepefic bile components. Impairment in the gene expression or function of HMTs may lead to intrahepatic cholestasis with or without bile duct injury. It has been reported that after OLT the composition of bile will change. Based on the above-mentioned results, we proposed the“toxic bile”hypothesis: After suffering CPRI, the protective mechanisms against bile salts cytotoxicity might be destroyed partly caused by the change of the gene expression and function of HMTs or other regulatory factors, which leads to the formation of“toxic bile”with excess hydrophobic bile salts. Therefore, a detailed systemic elucidation of the mechanism of the toxic bile formation is needed and will explore some new approaches for the prevention and treatment of biliary complications following OLT.
胆道并发症严重影响肝移植受者的生存及生活质量,被公认为肝脏移植的薄弱环节(Achilles’heel)。随着人们对胆道并发症认识的深化和外科吻合技术的提高,由外科技术原因造成的胆管吻合口并发症及引流管相关性并发症的发病率呈下降的趋势,而以非外科技术因素所导致的以移植物胆管树损害为主要特征的供体胆管并发症则成为术后胆道并发症的主要类型,发生率为2%-19%。以弥漫性或局灶性的移植物胆管树狭窄、扩张、毁损及管型形成为病理特征的缺血性胆管病变(ITBL)被认为是非外科性移植物胆管树损害的主要原因。尽管公认冷保存/再灌注损伤(CPRI)是其发病的主要因素,但具体机制尚不清楚。近年来,疏水性胆盐在胆道损伤中的作用受到人们的重视。疏水性胆盐既可以通过“去垢”(detergent)作用干扰生物膜的脂代谢,也可以诱导细胞调亡,具有很强的细胞毒性。人的胆盐池95%以上由疏水性胆盐组成。正常情况下,人类具有一套中和疏水性胆盐细胞毒性的自我保护机制,如磷脂可以与胆盐形成微胶粒(micelle)以降低其细胞毒性、胆汁所含的亲水性胆盐可以通过增强细胞膜的稳定性来对抗疏水性胆盐的细胞毒性等等。此外,胆汁主要成分的分泌完全依赖于位于肝细胞毛细胆管面的肝胆膜转运蛋白(HMTs),HMTs基因表达异常有可能导致胆汁淤积和胆管损伤。已经有研究提示肝移植术后早期存在胆汁成分失衡的现象。综合近年来国内外的研究结果,我们提出了移植肝冷保存/再灌注胆管损伤的“毒性胆汁”假说:在经历CPRI后,移植肝HMTs及相关调控因子的表达及功能可能出现改变,导致机体对抗疏水性胆盐毒性的保护性机制被破坏,形成具有较强细胞毒性的“毒性胆汁”,最终对胆管造成损伤。显然,如果我们能对该假说加以验证,必将加深对移植肝胆道并发症发生机制的认识,也有助于拓展新的预防和治疗策略。
二、目的
疏水性胆盐具有很强的细胞毒性,在胆管损伤中扮演着重要角色。本研究拟以验证“毒性胆汁”假说为主要目的,建立一种适于移植肝胆道问题研究的大鼠肝移植模型,探讨经历CPRI后移植肝胆汁主要成分的变化规律及与胆管损伤的相关性,并对
Background
Biliary complications after orthotopic liver transplantation(OLT) have been a common problem since early beginning of this technique, which have been called“the Achilles’heel”of OLT by Sir Roy Calne. With the improvement of surgical techniques, the incidence rate of the biliary complications associated with bile duct anastomosis decreased remarkably, while the nonanastomotic stricture and dilatation involving only the biliary tree of the graft with a radiological appearance of biliary ischemia(Ischemic-type biliary lesions, ITBL) become the major type of biliary complications after OLT, which has be reported to occur at a relatively constant rate 15-26%. It is well known that the cold preservation-reperfusion injury(CPRI) plays an important role in the pathegenesis of ITBL.However, the details still remain unclear despite numerous studies. Recently, it is reported that hydrophobic bile salts play a role in the pathogenesis of bile duct injury. The hydrophobic bile salts are cytotoxic due to their potent detergent properities toward cellular membranes. Under normal circumstances, some protective mechanisms can prevent the cytotoxcity of bile salts. For instance, bile salts can be neutralized in the bile by complex formation with phospholipid and some hydrophilic bile salts can stabilize cell membranes. In addition, various selective transporter proteins in the sinusoidal and canalicular membrane of hepatocytes(hepatobiliary membrane transporters, HMTs) have been identified and were shown to play a role in the secretion of sepefic bile components. Impairment in the gene expression or function of HMTs may lead to intrahepatic cholestasis with or without bile duct injury. It has been reported that after OLT the composition of bile will change. Based on the above-mentioned results, we proposed the“toxic bile”hypothesis: After suffering CPRI, the protective mechanisms against bile salts cytotoxicity might be destroyed partly caused by the change of the gene expression and function of HMTs or other regulatory factors, which leads to the formation of“toxic bile”with excess hydrophobic bile salts. Therefore, a detailed systemic elucidation of the mechanism of the toxic bile formation is needed and will explore some new approaches for the prevention and treatment of biliary complications following OLT.
引文
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1. 陈耿, 董家鸿. 移植肝冷保存/再灌注胆管损伤的机制. 中华外科杂志. 2006;44(9): 635-638
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13. Benedetti A, Alvaro D, Bassotti C et al. Cytotoxicity of bile salts against biliary epithelium: a study in isolated bile ductule fragments and isolated perfused rat liver.Hepatology;1997;26:9-21
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