Human liver transplantation is a major advance in medical science, but its application is limited due to the lack of adequate preservation techniques for the donor liver. The current method of preservation, namely flushing the donor liver with cold Collins solution followed by simple cold storage, adequately preserves the liver for 8-10 hours. This is not optimal because the transplant venture becomes dependent on transportation and does not allow for optimal histocompatability matching. It has been hypothesized that donor livers can be preserved for a longer time if an adequate means of maintaining the liver energy charge is available. In the current proposal, liver preservation will be examined in several ways. First, the hypothesis of better transplant function from higher donor hepatic energy charge will be tested by measuring ATP/Pi, lactate and pH levels of donor livers using nuclear magnetic resonance spectroscopy and correlating these levels with the patient's clinical course after the transplantation. Methods for increasing rat liver energy stores, and possibly decay rates, will be evaluated by altering pre-excisional oral and parenteral metabolic intake. Using a variety of cold preservation flush solutions and a variety of perfusates with a rat liver perfusion model, attempts will be made to develop a perfusion technique that will extend the preservation time of the excised rat livers. The energy state of the liver in these, as in the remainder of the experiments, will be monitored using MRS. Once it is established that adequate energy stores can be maintained or even increased, these artifically energy-enhanced livers will be tested in a transplant model using rats for improved function and survival compared to controls. In addition to studying new perfusates using the isolated rat perfusion model, the effects of ischemia on rat livers will be studied with particular reference to the metabolic changes noted in the liver by NMR spectroscopy, the biochemical changes in the liver as measured by traditional biochemical techniques on the liver perfusates before and after pass through the liver, and the histologic changes noted with ischemia over time. These three factors, metabolic, biochemical and histologic changes, will be correlated to further understand the pathophysiology of the liver during ischemia. From this new knowledge, better techniques for donor liver preservation with its associated benefits may be realized.
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