Human livers have been transplanted with dramatically increasing success during the past 5 years because of the improved immunosuppression provided by cyclosporin A. But the clinical option of transplantation is often reduced because donor livers can be safely preserved for only 6 to 10 hours. This limited preservation reduces the number of available livers, makes transplant surgery an emergency procedure requiring two surgical teams, and often necessitates operating on some of the sickest surgical patients (viz., liver transplant recipients) during the middle of the night. The proposed research is a comprehensive effort to improve the preservation of donor livers. We will use a dog model to: 1) define optimal conditions for continuous hypothermic perfusion (by examining the effects of perfusion pressures and the effects of administering the perfusate through the hepatic artery or portal vein, or both); 2) develop the ideal perfusate (by examining the roles of electrolyte ratio, oncotic pressure, and osmotic pressure derived from mannitol and raffinose); and 3) test drugs and other agents that minimize liver damage and facilitate the resumption of liver function after revascularization. The investigative agents will include enzyme inhibitors (allopurinol and EHNA), Ca channel blockers (nifedipine, diltiazem, and verapamil), O2-radical scavengers (SOD, catalase, mannitol, and desferrioxamine), membrane stabilizers (chlorpromazine and methylprednisolone) and prostacyclin. We will access cell viability, using an in vitro, tissue-slice model, and determine adenine nucleotide metabolism, O2 consumption, electrolyte transport, tissue edema, and protein synthesis. Cell structure will be assessed from histological analysis and electron microscopy. The viability of an organ and the integrity of its microcirculation will be assessed by orthotopic transplantation and by light and electron microscopic analyses of biopsy specimens. The initial perfusate will be one--which we recently developed for kidney preservation--that contains hydroxyethlstarch as the colloid, and adenosine, gluconate, phosphate, etc. The ultimate objective of this work is a method of clinically preserving donor livers for 48 to 72 hours that can be used in liver transplant programs.
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