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.
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