霉酚酸酯和雷帕霉素对大鼠肝脏缺血再灌注损伤的保护作用及其机制研究
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摘要
研究目的:
肝缺血再灌注损伤(ischemia reperfusion injury,I/R injury)是导致早期移植物失功的最常见原因之一,同时也是影响肝脏移植术后移植物长期存活的一个主要危险因素。而且对于逐渐广泛开展的边缘性供肝和活体供肝肝脏移植来说,由于供肝肝功能贮备相对较低,导致对缺血缺氧的耐受性更差,如何减轻肝脏缺血再灌注损伤已经成为此类供肝面临的主要问题。由于器官移植必然伴随有缺血再灌注损伤,而免疫抑制剂的使用对器官移植来说也同样不可避免,因此免疫抑制剂对器官缺血再灌注损伤的影响越来越受到国内外研究者的重视。近年来,霉酚酸酯和雷帕霉素被越来越多的应用于临床肝脏移植的免疫抑制方案中。因此,深入研究霉酚酸酯和雷帕霉素对肝脏缺血再灌注损伤的影响并进一步探讨和阐明其作用机理,不仅能增进我们对肝脏缺血再灌注损伤机制的理解,同时也对肝脏移植术后免疫抑制剂的选择和使用具有重要的临床指导意义。
研究方法:
通过大鼠肝脏缺血再灌注模型以及大鼠肝窦内皮细胞缺氧模型、原代大鼠肝窦内皮分离及厌氧培养模型,使用活体荧光、real-time PCR、western blot等方法,研究了霉酚酸酯和雷帕霉素对大鼠肝脏缺血再灌注损伤后肝脏损伤、氧自由基活化、肝脏再生等方面的作用,同时重点分析霉酚酸酯及雷帕霉素对肝脏缺血再灌注后微循环改变的影响,并从粘附分子以及相关信号转道通路等方面初步探讨其可能的作用机制。
研究结果:
本研究证实,大鼠肝脏缺血再灌注损伤时,粘附分子ICAM-1和VCAM-1在mRNA水平和蛋白水平的表达均有明显上调,并进一步介导了白细胞和内皮细胞间的粘附反应,导致肝脏微循环紊乱,造成肝功能受损。霉酚酸酯和雷帕霉素干预治疗不仅能够抑制缺血再灌注损伤后的氧自由基活化,同时能够分别通过下调MAPKs通路和mTOR通路的磷酸化来抑制粘附分子ICAM-1和VCAM-1的表达水平,从而缓解缺血再灌注引起的炎性细胞粘附聚集和肝窦微循环障碍。
研究结论:
霉酚酸酯和雷帕霉素能够有效缓解肝脏缺血再灌注损伤,其机理可能与它们抑制氧自由基释放及通过各自不同的信号传导通路下调了粘附分子的表达,导致炎性细胞和肝窦内皮细胞间的粘附作用减弱,从而改善了缺血再灌注后肝脏微循环障碍有关。
Objective:
Hepatic ischemia/reperfusion(I/R) injury is one of the most common causes of early allograft dysfunction in liver transplanted patients and represents an additional risk factor for long-term survival after transplantation.The destructive effects of I/R injury are the result of a complex pathophysiological process with a number of contributory factors.Previous investigations have shown that overproduction of reactive oxygen species and hepatic microcirculation disturbances,which are characterized by capillary perfusion failure and increased leukocyte adherence,are important aspects of hepatic I/R injury.By targeting these aspects,the development of pharmaceutical strategies to attenuate hepatic I/R injury is important for achieving better clinical outcomes.Previous evidence has indicated that immunosuppressive drugs,which are inevitably used in transplantation,have impacts on organ I/R injury.Mycophenolate mofetil and rapamycin are powerful immunosuppressants that are currently used for the prevention of acute organ graft rejection.Earlier experimental studies on renal ischemia have suggested mycophenolate mofetil and rapamycin can inhibit the overexpression of adhesion molecules and suppress leukocyte-endothelial cell interactions,which play central roles in I/R injury.In recent years,mycophenolate mofetil and rapamycin have been gradually introduced into clinical liver transplantation as immunosuppressive drugs.Since transplanted livers are subject to I/R injury,the potential effects of mycophenolate mofetil and rapamycin on the process of hepatic I/R injury are of considerable importance.However,the effects of mycophenolate mofetil and rapamycin on hepatic I/R injury and the potential mechanisms involved are still not totally understood.
Methods:
Using rat liver ischemia-reperfusion injury model,the effects of mycophenolate mofetil and rapamycin were evaluated by assessing liver damage,production of reactive oxygen species,postischemic liver regeneration.Expression of vascular cell adhesion molecule-1(VCAM-1),intercellular cell adhesion molecule-1(ICAM-1),as well as leukocyte-endothelial cell interactions in both the rat hepatic microcirculation and isolated liver sinusoidal endothelial cells was observed by intravital fluorescence microscopy and cell culture.Furthermore,activation of mitogen-activated protein kinases(MAPKs) and mammalian target of rapamycin(mTOR) were also investigated for understanding of the potential mechanisms.
Results:
Liver cell apoptosis and overproduction of reactive oxygen species were decreased by mycophenolate mofetil and rapamycin pretreatment.Mycophenolate mofetil and rapamycin also improved I/R-induced hemodynamic turbulence,as evidenced by reduced hepatic perfusion failure and decreased numbers of rolling and adherent leukocytes.I/R injury induced activation of MAPKs and mTOR pathways as well as overexpressed ICAM-1 and VCAM-1 was downregulated by mycophenolate mofetil and rapamycin pretreatment.
Conclusion:
In summary,mycophenolate mofetil and rapamycin attenuate hepatic I/R injury through suppression of the production of reactive oxygen species and amelioration of postischemic microcirculatory disturbances.
肝缺血再灌注损伤(ischemia reperfusion injury,I/R injury)是导致早期移植物失功的最常见原因之一,同时也是影响肝脏移植术后移植物长期存活的一个主要危险因素。而且对于逐渐广泛开展的边缘性供肝和活体供肝肝脏移植来说,由于供肝肝功能贮备相对较低,导致对缺血缺氧的耐受性更差,如何减轻肝脏缺血再灌注损伤已经成为此类供肝面临的主要问题。由于器官移植必然伴随有缺血再灌注损伤,而免疫抑制剂的使用对器官移植来说也同样不可避免,因此免疫抑制剂对器官缺血再灌注损伤的影响越来越受到国内外研究者的重视。近年来,霉酚酸酯和雷帕霉素被越来越多的应用于临床肝脏移植的免疫抑制方案中。因此,深入研究霉酚酸酯和雷帕霉素对肝脏缺血再灌注损伤的影响并进一步探讨和阐明其作用机理,不仅能增进我们对肝脏缺血再灌注损伤机制的理解,同时也对肝脏移植术后免疫抑制剂的选择和使用具有重要的临床指导意义。
研究方法:
通过大鼠肝脏缺血再灌注模型以及大鼠肝窦内皮细胞缺氧模型、原代大鼠肝窦内皮分离及厌氧培养模型,使用活体荧光、real-time PCR、western blot等方法,研究了霉酚酸酯和雷帕霉素对大鼠肝脏缺血再灌注损伤后肝脏损伤、氧自由基活化、肝脏再生等方面的作用,同时重点分析霉酚酸酯及雷帕霉素对肝脏缺血再灌注后微循环改变的影响,并从粘附分子以及相关信号转道通路等方面初步探讨其可能的作用机制。
研究结果:
本研究证实,大鼠肝脏缺血再灌注损伤时,粘附分子ICAM-1和VCAM-1在mRNA水平和蛋白水平的表达均有明显上调,并进一步介导了白细胞和内皮细胞间的粘附反应,导致肝脏微循环紊乱,造成肝功能受损。霉酚酸酯和雷帕霉素干预治疗不仅能够抑制缺血再灌注损伤后的氧自由基活化,同时能够分别通过下调MAPKs通路和mTOR通路的磷酸化来抑制粘附分子ICAM-1和VCAM-1的表达水平,从而缓解缺血再灌注引起的炎性细胞粘附聚集和肝窦微循环障碍。
研究结论:
霉酚酸酯和雷帕霉素能够有效缓解肝脏缺血再灌注损伤,其机理可能与它们抑制氧自由基释放及通过各自不同的信号传导通路下调了粘附分子的表达,导致炎性细胞和肝窦内皮细胞间的粘附作用减弱,从而改善了缺血再灌注后肝脏微循环障碍有关。
Objective:
Hepatic ischemia/reperfusion(I/R) injury is one of the most common causes of early allograft dysfunction in liver transplanted patients and represents an additional risk factor for long-term survival after transplantation.The destructive effects of I/R injury are the result of a complex pathophysiological process with a number of contributory factors.Previous investigations have shown that overproduction of reactive oxygen species and hepatic microcirculation disturbances,which are characterized by capillary perfusion failure and increased leukocyte adherence,are important aspects of hepatic I/R injury.By targeting these aspects,the development of pharmaceutical strategies to attenuate hepatic I/R injury is important for achieving better clinical outcomes.Previous evidence has indicated that immunosuppressive drugs,which are inevitably used in transplantation,have impacts on organ I/R injury.Mycophenolate mofetil and rapamycin are powerful immunosuppressants that are currently used for the prevention of acute organ graft rejection.Earlier experimental studies on renal ischemia have suggested mycophenolate mofetil and rapamycin can inhibit the overexpression of adhesion molecules and suppress leukocyte-endothelial cell interactions,which play central roles in I/R injury.In recent years,mycophenolate mofetil and rapamycin have been gradually introduced into clinical liver transplantation as immunosuppressive drugs.Since transplanted livers are subject to I/R injury,the potential effects of mycophenolate mofetil and rapamycin on the process of hepatic I/R injury are of considerable importance.However,the effects of mycophenolate mofetil and rapamycin on hepatic I/R injury and the potential mechanisms involved are still not totally understood.
Methods:
Using rat liver ischemia-reperfusion injury model,the effects of mycophenolate mofetil and rapamycin were evaluated by assessing liver damage,production of reactive oxygen species,postischemic liver regeneration.Expression of vascular cell adhesion molecule-1(VCAM-1),intercellular cell adhesion molecule-1(ICAM-1),as well as leukocyte-endothelial cell interactions in both the rat hepatic microcirculation and isolated liver sinusoidal endothelial cells was observed by intravital fluorescence microscopy and cell culture.Furthermore,activation of mitogen-activated protein kinases(MAPKs) and mammalian target of rapamycin(mTOR) were also investigated for understanding of the potential mechanisms.
Results:
Liver cell apoptosis and overproduction of reactive oxygen species were decreased by mycophenolate mofetil and rapamycin pretreatment.Mycophenolate mofetil and rapamycin also improved I/R-induced hemodynamic turbulence,as evidenced by reduced hepatic perfusion failure and decreased numbers of rolling and adherent leukocytes.I/R injury induced activation of MAPKs and mTOR pathways as well as overexpressed ICAM-1 and VCAM-1 was downregulated by mycophenolate mofetil and rapamycin pretreatment.
Conclusion:
In summary,mycophenolate mofetil and rapamycin attenuate hepatic I/R injury through suppression of the production of reactive oxygen species and amelioration of postischemic microcirculatory disturbances.
引文
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