Clinical lung transplantation (LTX) is severely limited by a shortage of suitable donors. Thus, hundreds of Americans die annually waiting for LTX, and thousands more with end stage respiratory disease are denied the opportunity of improved health that LTX may afford them. The lung is unique among solid organs in that it does not rely on perfusion for cellular respiration. We hypothesize that lung tissue remains viable for hours after circulatory arrest and death, and thus the lung may be suitable for transplantation, even if retrieved at substantial intervals after circulatory arrest and death of a non-heart beating organ donor (NHBD). We have substantiated this hypothesis with animal LTX experiments, which demonstrate that lungs retrieved at intervals after circulatory arrest may function well, but are affected adversely by ischemia-reperfusion injury (IRI). There is evidence that the cyclic nucleotide cAMP and cGMP are important mediators of altered endothelial permeability in lung IRI. IRI is associated with upregulation of endothelial cellular adhesion molecules (CAM) which recruit polymorphonuclear leukocytes (PMN) to the lung that contribute to IRI. We hypothesize that cyclic nucleotides play a pivotal role in maintaining endothelial cytoskeletal integrity, which in turn plays a role in CAM upregulation. This proposal aims to: 1) Characterize events that occur in the NHBD lung during the period of normothermic ischemia after circulatory arrest but prior to reperfusion. 2) Determine the relationship between CAMP and cGMP in lung tissue and pulmonary endothelial permeability changes due to IRI after circulatory arrest. 3) Determine the relationship between CAM expression, PMN recruitment, and lung function in transplanted lungs from NHBDs. Utilizing a rat isolated lung perfusion model and a rat LTX model, this proposal intends to achieve a better understanding of the molecular events involved in IRI and develop strategies that minimize lung injury in the setting of retrieval from NHBDs. This will facilitate the introduction of lung retrieval for transplant from NHBDs, which has the potential to extend the lives of thousands of Americans suffering with a variety of lung diseases.
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