MECHANISM(S) OF ALCOHOL-INDUCED LIVER GRAFT FAILURE

肝移植已经成为一种越来越被世界接受的治疗方法 对于患有不可逆肝病的儿童和成人。 不幸的是， 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导致的 酒精消耗导致的器官移植失败 因为 肝移植的来源主要是脑死亡的事故受害者， 酒精，脂肪肝， 移植后的移植物衰竭必须被理解，如果供体 可用器官库将扩大。 因此，这一目标 项目是确定和澄清机制参与失败的脂肪 肝脏和制定战略，以防止失败以下 移植 我们有独特的优势来进行这项研究，因为 我们的实验室在乙醇代谢方面有着丰富的经验， 以及啮齿类动物的肝脏移植。 我们计划确定 肝脏脂质含量与移植物衰竭之间存在因果关系 当在大鼠动脉化模型中乙醇含量保持恒定时， 肝移植 乙醇处理对移植物存活的影响 也将进行评估。 这些实验有望提供清晰的 有证据表明，移植失败和脂肪肝之间的因果关系 由于脂肪和/或乙醇的存在。 脂肪肝的发病机制 加剧了由于冷后再灌注损伤引起的脂质过氧化反应 将通过确定变化的时间过程来评估储存， 发生在术后。 对照组和乙醇处理组大鼠将 移植，氧，乙醇和脂质自由基将被捕获 术后使用自旋捕获技术， 电子自旋共振光谱学 肝线粒体功能和 将检查脂质含量以确定能量状态是否受损 肝脏脂质水平对移植失败至关重要。 此外，胆汁流动和 高度依赖于能量状态的尿素合成将被 监测。 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， 枯否细胞在再灌注后被激活到更大的程度， 脂肪肝比对照组。 视频显微镜将用于调查 脂肪肝患者的白色细胞粘附和微循环是否改变 肝脏 从这些研究中获得的信息将使我们能够开发 预防脂肪移植失败的特定机制策略 未来，如药物治疗的供体，以减少移植 脂质含量以及器官储存和冲洗溶液的改变。 这 信息将导致战略，这将增加可用的 肝移植，减少置换手术的需要， 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.