MECHANISM(S) OF ALCOHOL-INDUCED LIVER GRAFT FAILURE

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Liver transplantation has become an increasingly accepted therapy worldwide for children and adults with irreversible liver disease. Tragically, children die while on waiting lists because of organ shortages. One critical problem in liver transplantation is that fatty livers resulting from alcohol consumption fail when used as donor organs. Because the source of liver grafts is largely brain-dead accident victims where alcohol is heavily involved, the relationship between alcohol, fatty liver, and graft failure following transplantation must be understood if the donor pool of usable organs is to be expanded. Therefore, the goals of this project are to identify and clarify mechanisms involved in failure of fatty livers and to develop strategies to prevent failure following transplantation. We are uniquely positioned to perform this research since our laboratory has extensive experience both with ethanol metabolism as well as with rodent liver transplantation. We plan to determine if a causal relationship between hepatic lipid content and graft failure exists when ethanol content is held constant in the arterialized model of rat liver transplantation. The effect of ethanol treatment on graft survival will also be evaluated. These experiments are expected to provide clear evidence that a causal relationship between graft failure and fatty liver due to fat and/or ethanol exists. The hypothesis that fatty liver exacerbates lipid peroxidation due to reperfusion injury following cold storage will be evaluated by determining the time course of changes which occur postoperatively. Control and ethanol-treated rats will be transplanted, and oxygen, ethanol and lipid free radicals will be trapped postoperatively using the spin-trapping technique and quantitated using electron spin resonance spectroscopy. Hepatic mitochondrial function and lipid content will be examined to determine if energy state is compromised by hepatic lipid levels critical for graft failure. Further, bile flow and urea synthesis, which are highly dependent on energy state, will be monitored. We will also use electron microscopy to evaluate the time course of changes in endothelial cells of fatty liver to determine if they are particularly vulnerable to cold storage and reperfusion injury and if Kupffer cells are activated to a greater extent following reperfusion of fatty livers than controls. Video microscopy will be used to investigate whether white cell adhesion and microcirculation are altered in fatty livers. Information gained from these studies will allow us to develop specific mechanism-based strategies to prevent failure of fatty grafts in the future, such as pharmacological treatment of the donor to reduce graft lipid content and modification of organ storage and rinse solutions. This information will lead to strategies which will increase the pool of usable liver grafts, decrease the need for replacement surgery and minimize postoperative complications markedly.