Defatting of steatotic liver grafts by normothermic ex vivo machine perfusion with DNP

肝移植是终末期肝病的治疗选择，但潜在受体的数量不断超过器官供应。为了增加可用肝移植的数量，使用所谓的边缘同种异体肝移植。不幸的是，这些器官的移植与移植物功能延迟、原发性功能障碍、移植物和患者存活率降低有关。肝脂肪炎是移植物术后功能障碍的重要危险因素。大泡性脂肪变性超过60%的肝移植通常会被丢弃，并且假定由于普通人群中脂肪性肝炎的患病率上升，肝移植的总体利用率将显著下降。在文献中，通过机器灌注的肝脏脱脂已被提出作为调节脂肪变性肝移植的概念。然而，脱脂移植物移植的结果尚未见文献报道，可能与所使用的药物和灌注条件有关。假设体外机器灌注DNP能降低脂肪变性肝移植物肝内脂肪含量，且对移植物无不良影响。DNP导致轻度线粒体解偶联。在前期工作中，申请人建立了大鼠肝脏恒温离体机器灌注模型，并取得了DNP对肝脏脱脂的初步结果。拟议拨款申请的目的是确定在恒温灌注条件下用DNP脱脂的最佳条件。将在肝移植大鼠模型中对脱脂肝移植进行体内评价。脱脂肝将被广泛表征，以排除脱脂方案的不利影响。为了证明用DNP进行肝脏脱脂可以成功地转化为临床，将与德国器官移植基金会（Deutsche Stiftung Organtransplantation， DSO）合作进行一项实验性研究，研究因大泡性脂肪变性而移植排斥的人肝移植物的脱脂。

Liver transplantation is the treatment of choice for end-stage liver disease, but the number of potential recipients constantly exceeds the organ supply. In order to increase the number of available liver grafts, so-called marginal liver allografts are used. Unfortunately, transplantation of these organs is associated with delayed graft function, primary dysfunction, and lower graft and patient survival rates. Steatotis hepatis is an important risk factor for postoperative graft dysfunction. Liver grafts with macrovesicular steatosis above 60% are usually discarded and it is assumed that the overall liver graft utilization will noticeable fall due to the rising prevalence of steatotis hepatis in the general population. Liver defatting by machine perfusion has been proposed as a concept for conditioning of steatotic liver grafts in literature. However, results of transplantation of defatted grafts are not available in literature, presumably due to the applied agents and perfusion conditions. It is hypothesized that normothermic ex vivo machine perfusion with DNP can decrease the intrahepatic fat content of steatotic liver grafts without adverse effects on the graft. DNP leads to mild mitochondrial uncoupling. In preliminary work, the applicants developed a model for normothermic ex vivo machine perfusion of rat livers and achieved first results on liver defatting with DNP. The objectives of the proposed grant application are to define optimal conditions for defatting with DNP under normothermic perfusion conditions. Transplantation of defatted liver grafts will be evaluated in vivo in a rat model of liver transplantation. Defatted livers will be extensively characterized in order to exclude adverse effects of the defatting protocol. In order to demonstrate that liver defatting with DNP can be successfully translated into the clinic, a pilot study will be performed in cooperation with the German Organ Transplantation Foundation (Deutsche Stiftung Organtransplantation, DSO) on defatting of human liver grafts rejected from transplantation due to macrovesicular steatosis.