LIVER PRESERVATION FOR CLINICAL TRANSPLANTATION

临床移植的肝脏保存

• 批准号: 2838080
• 负责人: James H. Southard
• 金额: $ 24.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2838080
• 关键词: adenine nucleotides; antioxidants; cell death; cell population study; cryopreservation; cryoprotective agents; disease /disorder model; dogs; electron microscopy; free radical oxygen; histology; hypothermia; laboratory rat; liver cells; liver metabolism; liver preservation; liver transplantation; method development; nucleotide metabolism; organ culture; perfusion; phospholipase inhibitor; protease inhibitor

Liver transplantation (LTx) is accepted therapy for various liver diseases. However, there are two problems: primary nonfunction (PNF) and shortage of livers. PNF, caused by preservation or reperfusion injury, necessitates a retransplant. This contributes to the shortage of livers. PNF contributes to the enormous cost of LTx and significant patient discomfort. Improving preservation of the liver would contribute significantly to improved results in LTx. Our goals in this project are to improve liver preservation to reduce PNF, decrease cost, decrease shortage of livers and deaths on the waiting list, provide a method to judge viability of the liver, and increase utilization of marginal livers (ischemic). We hypothesize that significant improvements in liver preservation will require continuous hypothermic machine perfusion (HMP). We shall demonstrate the feasibility of excellent quality, long-term liver preservation by HMP accomplishing these five specific aims: 1) optimize the method of liver perfusion, 2) optimize the perfusate specifically for the liver, 3) enhance preservation with cytoprotective agents previously shown to decrease liver injury, 4) develop a viability assay based on liver hypothermic metabolism, and 5) optimize HMP of the liver to salvage marginal (ischemically injured) livers. How these research strategies affect the quality and longevity of liver preservation will be judged by survival in the orthotopic rat liver transplant model (OLTx) and the degree of metabolic injury.using the isolated perfused liver (IPL). Integrity of the microvascular system and sinusoids will be assessed by electron microscopy. Strategies that show significant enhancement of rat liver preservation will be confirmed in the dog liver Tx model. The new information generated will lead to a more comprehensive understanding of liver preservation/reperfusion injury, develop a new state-of-the-art for liver preservation, provide measures of liver viability during HMP, and increase the donor pool by salvaging marginal livers. Successful HMP could have a dramatic effect on the outcome of clinical LTx and become the technique of choice in large transplant centers such as ours.

肝移植（LTx）是治疗各种肝病的有效方法 疾病然而，存在两个问题：原发性无功能（PNF）和 肝脏短缺。PNF由保存或再灌注损伤引起， 需要再次移植这导致了肝脏的短缺。 PNF导致了LTx的巨大成本和重大患者 不适改善肝脏的保存将有助于 显著改善LTx的结果。 我们在这个项目中的目标是 改善肝脏保存以减少PNF，降低成本， 肝脏短缺和等待名单上的死亡，提供了一种方法， 判断肝脏的活力，增加边缘肝脏的利用率 （缺血性）。我们假设肝脏的显著改善 保存将需要持续低温机器灌注（HMP）。 我们将展示卓越品质的可行性，长期 通过HMP实现以下五个具体目标：1） 优化肝脏灌注方法; 2）优化灌注液 特别是对肝脏，3）增强保存与细胞保护 先前显示可减少肝损伤的药物，4）发展成 基于肝脏低温代谢的测定，和5）优化HMP的 肝脏以挽救边缘（缺血损伤）肝脏。如何将这些 研究策略影响肝脏的质量和寿命 保存将通过原位大鼠肝脏中的存活率来判断 移植模型（OLTx）和代谢损伤的程度。 离体灌注肝（IPL）。微血管系统的完整性， 通过电子显微镜评估窦状隙。战略表明， 将证实大鼠肝脏保存的显著增强， 狗肝Tx模型。产生的新信息将导致更多的 全面了解肝脏保存/再灌注损伤， 发展一种新的肝脏保存技术， HMP期间的肝脏活力，并通过挽救 边缘肝成功的HMP可能会对 临床LTx的结果，并成为大规模 像我们这样的移植中心