An important factor in preventing necrosis of transplanted liver is the ability to limit ischemia/reperfusion injury in the transplanted organ. Recent studies have established that the generation of superoxide is a critical component of ischemia/reperfusion injury in the liver. The primary source of superoxide (during reperfusion) in this tissue appears to be the enzyme xanthine oxidase. It has been proposed that xanthine oxidase is generated in ischemic tissues by conversion of native xanthine dehydrogenase, which produces is critical to the damage process.
The aims of this proposal are: 1) to examine the importance of the conversion process in xanthine oxidase-mediated tissue injury in the ischemic/reperfused liver determining both the contribution of xanthine oxidase to total injury and the role of conversion in that damage, 2) to determine the mechanism of dehydrogenase to oxidase conversion in ischemic tissues examining both the processes of DTT-reversible conversion mediated by sulphydryl modification (possibly GSSG-mediated) and irreversible conversion-mediated by intracellular proteases, and 3) to examine variations in cellular antioxidant systems during ischemia that might influence tissue injury. It is hoped that these studies will provide a basis for further development of rationale pharmacological approaches to tissue preservation.
