PHARMACOLOGIC AGENTS FOR PRESERVATION OF DONOR LIVERS

由于自2000年以来，对器官排斥的控制得到了极大的改善， 环孢菌素A的引入，肝移植已经成为一种 某些肝病的公认治疗形式。 但 肝脏对局部缺血的相对不耐受性仍然是一个 器官可用性和移植物存活的限制因素。 先前 克服这个问题的尝试包括使用 低温、细胞内型溶液和各种灌注 技术. 虽然在这方面取得了重大进展， 允许的缺血时间还没有到来，因为 最近的研究表明， 改善肝脏病理的几个可能领域 缺血和再灌注后可能会出现。 最 重要的因素似乎是恢复能源平衡， 防止再灌注过程中有毒物质的产生。 的 拟议的研究将集中在第一个因素-平衡 缺血/再灌注期间能量（O2）供应和需求之间的关系 在离体灌流的大鼠肝脏中。 这些参数可以 通过控制肝脏代谢和微循环 血流 我们假设，这些特定的操纵 通过药理学以及其他手段， 改善细胞和器官稳态并最终改善移植物 移植后存活率。 具体来说，实验 旨在评估肾上腺素能阻滞剂的使用情况， 在隔离期间保存细胞能量储存。 此外，在保存期结束时， 将控制再灌注液的含量和温度， 确定最小化细胞的最佳条件， 损伤 一个潜在的非常重要的，但在很大程度上尚未开发的 在再灌注期间O2供应到肝脏的决定因素是 微循环的完整性。 因此， 微血管损伤将使用形态测量和 活体技术和损伤机制， 实质细胞、枯否细胞和血液的贡献 将对各组成部分进行研究。 使用这种离体灌注大鼠 用于评价肝功能的肝脏模型将提供 用于评估上述内容的可靠且具有成本效益的手段 原则作为其在大型动物中评价的前奏 移植模型 因此，这种方法应确定改进的 肝脏保存技术可以快速应用于 临床移植

Because of the vastly improved control of organ rejection since the introduction of Cyclosporin A, liver transplantation has become an accepted form of therapy for certain liver diseases. However, the relative intolerance of the liver to ischemia continues to be a limiting factor in organ availability and graft survival. Previous attempts at overcoming this problem have included the use of hypothermia, intracellular-type solutions and various perfusion techniques. Although major advances in this prolongation of allowable ischemic time have not been forthcoming since the introduction of the use of hypothermia, recent studies suggest several possible areas where amelioration of hepatic pathology following ischemia and reperfusion might be expected. The most important factors appear to be restoration of energy balance and prevention of toxic substance generation during reperfusion. The proposed studies will focus on the first factor - the balance between energy (02) supply and demand during ischemia/reperfusion in the isolated perfused rat liver. These parameters can be manipulated by controlling liver metabolism and microcirculatory blood flow. We hypothesize that specific manipulation of these areas by pharmacologic, as well as other means will significantly improve cellular and organ homeostasis and ultimately improve graft survival following transplantation. Specifically, the experiments are designed to evaluate the uss of adrenergic blockade for the preservation of cellular energy stores during isolation. Additionally, at the end of this preservation period, oxygen content and temperature of the reperfusate will be controlled to determine the optimal conditions for the minimization of cellular injury. A potentially very important but largely unexplored determinant of 02 supply to the liver during reperfusion is integrity of the microcirculation. Thus, the nature and extent of microvascular damage will be quantified using morphometric and intravital techniques and the mechanisms of injury with respect to the contributions of parenchymal cells, Kupffer cells and blood components will be studied. The use of this isolated perfused rat liver model for evaluation of liver function will provide a reliable and cost effective means for evaluating the above principles as a prelude to their evaluation in large animal transplant models. Thus, this approach should identify improved liver preservation techniques that can be quickly applied to clinical transplantation.