application) Human liver transplantation is regularly performed for end-stage liver disease, but cellular damage resulting from hypothermic ischemic storage of warm oxygenated reperfusion still results in significant postimplantation morbidity. The mechanisms of this injury and methods for their prevention are the principal research interests of this laboratory. Using P-31, Na-23, and F-19 NMR spectroscopy of perfused mouse livers under various preservation and reperfusion conditions, the investigators will obtain serial estimates of liver energy content, compartmental fluxes of Na+ and intracellular pH, which are all sensitive indicators of hypoxic and ischemic injury. These studies will be complemented with biochemical and histological studies and in-vivo video microscopy of livers to document changes in endothelial and Kupffer cells and in sinusoidal perfusion during storage and reperfusion. The applicants will measure hepatic ATP levels using localized P-31 NMR spectroscopy of rat livers in vivo and in rat livers during storage and perfusion following nutritional manipulations to document whether donor nutritional manipulation enhances liver energy content. Thereafter, livers prepared according to results of these studies will be used in a model of rat liver transplantation. The applicants hope to define optimal conditions for human liver preservation and subsequent implantation. Following transplantation, liver function and histology of short- and long-term survivor rats will be compared by in-vivo NMR determination of ATP fluxes and HPLC analysis of adenine nucleotides. These experiments will help delineate optimal preservation conditions and sequential changes occurring during development of organ rejection or other transplant-related complications and may help differentiate between ischemia and rejection. Then P-31 NMR spectra of human livers acquired immediately prior to implantation will be correlated with clinical outcome and adenine nucleotide content of biopsy samples, evaluating the potential role of spectroscopy as a screening procedure for donor livers.
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