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

肝移植是终末期肝病的首选治疗方法，但潜在受体的数量不断超过器官供应。为了增加可用的肝移植的数量，使用了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、原发功能障碍以及移植物和患者存活率降低有关。脂肪炎是术后移植物功能障碍的重要危险因素。大泡状脂肪变性超过60%的移植肝通常被丢弃，并假设由于脂肪炎在普通人群中的患病率上升，移植肝的总体利用率将显着下降。在文献中，通过机器灌流的肝脏脱脂被认为是脂肪变性肝移植物调理的一个概念。然而，文献中没有脱脂移植物移植的结果，可能是由于应用的试剂和灌流条件的原因。推测常温体外机械灌流DNP可降低脂肪变性肝移植物的肝内脂肪含量，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，申请者开发了常温体外机器灌流大鼠肝脏的模型，并在使用DNP进行肝脏脱脂方面取得了初步结果。建议拨款申请的目的是确定在常温灌流条件下使用DNP进行脱脂的最佳条件。脱脂肝移植将在大鼠肝移植模型中进行体内评估。将对脱脂肝脏进行广泛的表征，以排除脱脂方案的不利影响。为了证明使用DNP的肝脏脱脂可以成功地移植到临床上，将与德国器官移植基金会(Deutsche Stiftung Organantation，DSO)合作进行一项关于因大囊泡脂肪变性而被拒绝移植的人肝移植的初步研究。

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.