LIVER PRESERVATION FOR CLINICAL TRANSPLANTATION

这项工作的长期目标是开发一种更好的方法 保存人类肝脏用于移植。这样做的后果 将会是：为死于末期肝脏的患者提供更多的肝脏 疾病，移植肝脏数量减少 原发性无功能或移植物功能延迟，能力增加 对于国家（或国际）尸体肝脏共享而言， 通过减少肝移植的需要来降低肝移植的成本 再次移植和患者住院 (ICU) 的时间长短。 目前，威斯康星大学 (UW) 解决方案是标准 用于肝脏保存的保存液。我们将使用这个解决方案 开发改进的保存解决方案和方法的基础 保存（简单冷藏和连续机器灌注）。的 这项研究的具体目的是了解其机制 肝脏低温储存引起的细胞损伤 知识开发改进的保存方法。我们将研究 大鼠肝细胞和兔肝低温损伤机制 孤立灌注模型。我们将研究 ATP 的前体和 谷胱甘肽的合成影响保存、钙的作用 磷脂脂肪酶在保存损伤中的作用以及各种药物的影响 保护肝脏。此外，我们还将深入了解 通过研究保存损伤的重要性 UW 解决方案的各种组件以及如何添加不同的组件 UW 溶液中的药物和代谢物会影响 UW 溶液的质量和持续时间 肝脏保存。我们将确定保存如何影响能量 肝脏的产生能力以及如何清除氧自由基 影响保存质量。我们还将研究捐赠者因素如何影响 肝脏保存，特别是捐赠者的营养状况。 改善肝细胞代谢和肝功能的方法将是 在狗原位移植模型中进行测试以确定这些方法是否有效 转化为更具临床相关性的肝脏保存模型。 改善实验室肝脏保存的方法将用于 人类肝脏保存。

The long range objective of this work is to develop a better method to preserve the human liver for transplantation. The consequences of this would be: more livers available for patients dying from end stage liver diseases, a decrease in the number of transplanted livers that develop primary non-function or delayed graft function, increase in capabilities for national (or international) sharing of cadaveric livers, a decrease in the cost of liver transplantation by reducing the need for retransplantation and the length of hospital (ICU) stay of the patient. Currently, the University of Wisconsin (UW) solution is the standard preservation solution for liver preservation. We will use this solution as the basis for developing improved preservation solutions and methods of preservation (simple cold storage and continuous machine perfusion). The specific aims of this study are to gain an understanding of the mechanisms of cellular injury caused by hypothermic storage of the liver and with this knowledge develop improved preservation methods. We will study the mechanisms of hypothermic injury using a rat hepatocyte and rabbit liver isolated perfusion model. We will study how precursors of ATP and glutathione synthesis affect preservation, the role of calcium and phospholipid lipases in preservation injury and how various drugs affect the preservation of the liver. Additionally, we will gain insight into the mechanism of preservation injury by investigating the importance of the various components of the UW solution and how the addition of different drugs and metabolites to the UW solution affect the quality and duration of liver preservation. We will determine how preservation affects the energy generating capabilities of the liver and how oxygen free radical scavengers affect preservation quality. We will also study how donor factors affect liver preservation, specifically the nutritional status of the donor. Methods that improve liver cell metabolism and liver functions will be tested in the dog orthotopic transplant model to determine if these methods translate to a more clinically relevant model of liver preservation. Methods that improve liver preservation in the laboratory will be used for human liver preservation.