PHARMACOLOGIC AGENTS FOR PRESERVATION OF DONOR LIVERS

因为器官排斥反应的控制自 环孢素A的引入，肝移植已成为一种 为某些肝病接受的一种治疗形式。然而， 肝脏对缺血的相对不耐受仍然是一种 器官可获得性和移植物存活率的限制因素。上一首 克服这一问题的尝试包括使用 低温、细胞内型溶液和各种灌流 技巧。虽然在这一延长时间方面的主要进展 允许的缺血时间没有到来，因为 最近的研究表明，低温疗法的使用已被引入 肝脏病理改善的几个可能领域 在缺血和再灌流后，可能是可以预期的。最多的 重要因素似乎是恢复能源平衡和 防止再灌流期间有毒物质的产生。这个 拟议的研究将侧重于第一个因素--平衡 缺血/再灌流期间能量(02)供需之间的关系 在隔离灌流的大鼠肝脏中。这些参数可以是 通过控制肝脏代谢和微循环来操纵 血液流动。我们假设对这些的特定操作 通过药理学以及其他手段，这些领域将显著 改善细胞和器官动态平衡，最终改善移植物 移植后的存活率。具体来说，这些实验 旨在评估肾上腺素能受体阻滞剂对 隔离期间细胞能量储存的保存。 此外，在保存期结束时，氧气 再灌流液的含量和温度将控制在 确定元胞极小化的最优条件 受伤。一个潜在的非常重要但在很大程度上尚未探索的 在再灌流期间供肝的决定因素是 微循环的完整性。因此，它的性质和范围 微血管损伤将使用形态测量和 生命中的技术和损伤的机制 实质细胞、库普弗细胞和血液的贡献 将对组件进行研究。这种隔离灌流大鼠的使用 用于评估肝功能的肝脏模型将提供一个 评估上述内容的可靠且经济高效的方法 原理作为在大型动物身上进行评价的前奏 移植模型。因此，这种方法应该确定改进的 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.