Liver transplant preservation injury represents a """"""""cold"""""""" ischemia/reperfusion (I/R) injury. Patients receiving livers with severe preservation injury exhibit significant increases in the length of ICU stay, infection, renal failure, biliary strictures, and allograft rejection. A profound arginine-deficient state occurs post-transplant due to arginase release from the injured liver graft. We believe arginine is critical for early hepatic protection, mediated in part by NO synthesis, and that arginine deficiency further contributes to ongoing liver graft injury. L-arginine supplementation does not result in increased circulating arginine levels and achieves only modest improvement in liver injury. Therefore, we hypothesize that inhibition of arginase will be required to enhance arginine availability and minimize damage resulting from liver preservation injury. This is a completely novel approach to combat organ injury; essentially nothing is known about the effects of arginase blockade in vivo. Preliminary data with injection of the arginase inhibitor, Nu-hydroxy-nor-L-arginine (nor-NOHA), showed that serum arginase activity was inhibited and circulating arginine levels were restored. This resulted in a significant decrease in liver enzyirie release and improvement in liver histology. In this proposal, we will pursue two aims to characterize arginine metabolism post-transplant and determine the effects of arginase blockade on liver cold I/R injury:
AIM I : TO DETERMINE WHETHER ENHANCING ARGININE AVAILABILITY THROUGH ARGINASE BLOCKADE PREVENTS LIVER TRANSPLANT ISCHEMIA/REPERFUSION INJURY. We will characterize arginine metabolism post-transplant and determine if arginine transport is modified during liver I/R injury. The effects of arginase blockade on serum and tissue arginine levels will be determined. The conditions that optimize arginine availability to maximize organ protection will be established. The potential adverse consequences of arginase inhibition on polyamine/proline synthesis, urea excretion, blood pressure, and alloimmurie response will be investigated.
AIM II : TO IDENTIFY THE MECHANISMS OF PROTECTION MEDIATED BY IMPROVING ARGININE AVAILABILITY ON LIVER GRAFT INJURY. We will determine if the beneficial effects of enhanced arginine availability are mediated by NO synthesis. The secondary mechanisms of tissue protection will be identified including the effects of enhanced arginine concentration on neutrophil infiltration, cytokine release, apoptosis, ultrastructural damage, hepatic blood flow, and HO-1 expression. The information gained will increase our understanding of the molecular pathophysiology of liver graft injury, and will provide completely new information regarding the in vivo effects of arginase blockade. We expect these findings to have broad implications far beyond transplant preservation injury that may be applicable to any form of liver injury resulting in hepatocellular arginase release and arginine depletion.
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