A clinical program has been developed that includes single lung transplantation for end-stage pulmonary fibrosis, double lung transplantation for emphysema and crystic fibrosis, and combined lung-heart transplantation for individuals with end-stage lung disease combined with irreversible right heart failure. This recent clinical success has generated an urgent need to increase the supply of donor organs, and the development of techniques for reliably diagnosing pulmonary injury following transplantation. We believe that lung dysfunction developing within the first 3 days of lung transplantation, the so-called """"""""reimplantation response"""""""", is in fact a manifestation of ischemia-reperfusion injury to the transplanted lung. We hypothesize that this injury can be ameliorated significantly by altering the preservation techniques used during the ischemic pretransplantation period. Parameters currently in use to evaluate lung in vivo are both non- specific and insensitive. The function of a single transplanted lung has been especially difficult to assess, since previously available techniques only evaluate the overall function of both the native and the tranplanted lung and not regional function. We hypothesize that this type of injury can be evaluated with serial measurements of pulmonary vascular permeability, extravascular water, and lung metabolism, as measured by the quantitative non- invasive nuclear medicine imaging technique of positron emission tomography, and with specific biochemical markers from bronchoalveolar lavage of tranplanted lung. Thus, the specific aims of this proposal are: 1) to document the prevalence of pulmonary vascular injury to transplanted lungs in animals and man; and 2) to investigate the effect of changing preservation techniques on the development of early lung injury after transplantation. To accomplish these goals, we plan to use established animals models of lung transplantation, as well as human subjects. Measurements will be made on the day of lung transplantation and 72 hrs after transplantion. In animals, correlations will also be made with pulmonary function and post-mortem histopathology. In humans, correlations will be made with pulmonary function, hemodynamics, and radiologic changes. The specific preservation techniques to be tested will be guided by data from the studies, including those from a recently developed ex-vivo isolated rabbit lung model. Based on preliminary work, testable preservation techniques will include calcium-channel blockers, oxygen free radical scavengers, and flushing with electrolyte solutions of extracellular composition. These studies could have a profound effect on lung transplanation strategies. Significant extension of preservation time (to say 12 hrs) would increase the number of possible transplants for patients with otherwise fatal pulmonary illnesses.
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