MECHANISM OF ALCOHOL-INDUCED LIVER GRAFT FAILURE

肝移植已成为世界范围内一种日益被接受的治疗方法。 适用于患有不可逆转肝病的儿童和成人。可悲的是， 由于器官短缺，儿童在等待名单上死亡。一 肝移植的关键问题是脂肪肝 当被用作捐献器官时，酒精消耗会失败。因为 肝移植的来源主要是脑死亡事故受害者，酒精 与酒精、脂肪肝和 必须了解移植后的移植物衰竭，如果供者 可使用的器官池将被扩大。因此，这一行动的目标是 该项目旨在确定和阐明FAT失败的机制 并制定策略，以防止以下失败 移植。我们处于独特的地位来进行这项研究，因为 我们的实验室在乙醇代谢方面拥有丰富的经验 啮齿动物肝脏移植也是如此。我们计划确定一个 肝脂含量与移植失败之间存在因果关系 大鼠动脉化模型中乙醇含量恒定的实验研究 肝脏移植。乙醇处理对移植物存活的影响 也将接受评估。预计这些实验将提供明确的 移植物衰竭和脂肪肝之间的因果关系的证据 由于脂肪和/或乙醇的存在。脂肪肝的假说 加重感冒后再灌流损伤所致的脂质过氧化 将通过确定下列更改的时间进程来评估存储 发生在手术后。对照组和酒精处理组大鼠将 移植后，氧、乙醇和脂质自由基将被捕获 术后使用自旋捕获技术，并定量使用 电子自旋共振谱。肝线粒体功能和 将检查脂肪含量以确定能量状态是否受到影响 由对移植失败至关重要的肝脂水平决定。此外，胆汁流量和 尿素合成高度依赖于能量状态，将是 被监视着。我们还将使用电子显微镜来评估时间 脂肪肝内皮细胞的变化过程以确定它们是否 特别容易受到冷藏和再灌注损伤的影响，如果 Kupffer细胞在再灌流后被更大程度地激活 比对照组的脂肪肝。视频显微镜将被用来研究 脂肪患者白细胞黏附和微循环是否发生改变 肝脏。从这些研究中获得的信息将使我们能够开发出 预防脂肪移植物失败的特殊机制策略 未来，如对供者进行药物治疗以减少移植物 脂肪含量和器官储存液及漂洗液的改性。这 信息将导致战略，从而增加可用资源池 肝移植，减少对替代手术的需要，并将 术后并发症明显。

Liver transplantation has become an increasingly accepted therapy worldwide for children and adults with irreversible liver disease. Tragically, children die while on waiting lists because of organ shortages. One critical problem in liver transplantation is that fatty livers resulting from alcohol consumption fail when used as donor organs. Because the source of liver grafts is largely brain-dead accident victims where alcohol is heavily involved, the relationship between alcohol, fatty liver, and graft failure following transplantation must be understood if the donor pool of usable organs is to be expanded. Therefore, the goals of this project are to identify and clarify mechanisms involved in failure of fatty livers and to develop strategies to prevent failure following transplantation. We are uniquely positioned to perform this research since our laboratory has extensive experience both with ethanol metabolism as well as with rodent liver transplantation. We plan to determine if a causal relationship between hepatic lipid content and graft failure exists when ethanol content is held constant in the arterialized model of rat liver transplantation. The effect of ethanol treatment on graft survival will also be evaluated. These experiments are expected to provide clear evidence that a causal relationship between graft failure and fatty liver due to fat and/or ethanol exists. The hypothesis that fatty liver exacerbates lipid peroxidation due to reperfusion injury following cold storage will be evaluated by determining the time course of changes which occur postoperatively. Control and ethanol-treated rats will be transplanted, and oxygen, ethanol and lipid free radicals will be trapped postoperatively using the spin-trapping technique and quantitated using electron spin resonance spectroscopy. Hepatic mitochondrial function and lipid content will be examined to determine if energy state is compromised by hepatic lipid levels critical for graft failure. Further, bile flow and urea synthesis, which are highly dependent on energy state, will be monitored. We will also use electron microscopy to evaluate the time course of changes in endothelial cells of fatty liver to determine if they are particularly vulnerable to cold storage and reperfusion injury and if Kupffer cells are activated to a greater extent following reperfusion of fatty livers than controls. Video microscopy will be used to investigate whether white cell adhesion and microcirculation are altered in fatty livers. Information gained from these studies will allow us to develop specific mechanism-based strategies to prevent failure of fatty grafts in the future, such as pharmacological treatment of the donor to reduce graft lipid content and modification of organ storage and rinse solutions. This information will lead to strategies which will increase the pool of usable liver grafts, decrease the need for replacement surgery and minimize postoperative complications markedly.