The proposed studies are designed to improve the supply of donor lungs for transplantation by developing technique to prolong the period of safe preservation following extraction. These specific goals of the project are: 1) To utilize newly developed animal models for testing lung viability and function, following preservation; 2) To systematically modify the conditions of preservation to determine the optimum method; 3) To study metabolic and biochemical alterations occurring during lung ischemia and reperfusion in order to increase understanding of the effects of ischemia and reperfusion, and from this, develop new interventions to improve lung preservation. A relatively inexpensive animal screening model has been developed, using ex-vivo perfusion of excised rabbit lungs. This screening model has been improved further by utilizing a donor rabbit as a source of blood for continuous perfusion through the isolated lungs and back into the rabbit, thus extending the period of reperfusion of the isolated lungs following their preservation. This model allows the donor rabbit to pre-treated in various ways with pharmacologic agents in order to attempt to modify the effects of reperfusion on the preserved lungs. The rabbit screening model will be used to study parameters thought to have an influence on lung preservation. Optimum techniques of preservation will be identified and applied in a lung transplant model in dogs in order to more closely simulate the clinical situation. Once methods for safety preserving lungs for 12 hours or more have been developed, techniques will be applied to a survival model of double-lung transplantation in baboons. Nuclear magnetic resonance spectroscopy (NMR) will be utilized to assay in high energy phosphate levels (ATP, ADP), glucose metabolism, and intracellular pH which occur during preservation and reperfusion of lungs. Periodic re-flushing of stored lungs to restore pH, glucose, and high energy phosphates will be evaluated in terms of the effect on metabolism and the effect on function of the preserved lungs.
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