ISCHEMIC INJURY IN CADAVER DONORS FOR LUNG TRANSPLANT

临床肺移植（LTX）由于缺乏合适的供体而受到严重限制。 因此，每年有数百名美国人死于等待LTX，还有数千名患有终末期呼吸道疾病的人被剥夺了LTX可能为他们提供的改善健康的机会。 肺在实体器官中是独特的，因为它不依赖于细胞呼吸的灌注。我们假设肺组织在循环停止和死亡后数小时内仍有活力，因此肺可能适合移植，即使在无心跳器官供体（NHBD）循环停止和死亡后相当长的时间间隔内取出。 我们已经证实了这一假设与动物LTX实验，这表明，肺回收循环停止后的间隔可能功能良好，但受到缺血再灌注损伤（IRI）的不利影响。 有证据表明，环核苷酸cAMP和cGMP是肺IRI中内皮通透性改变的重要介质。 IRI与内皮细胞粘附分子（CAM）的上调有关，CAM将多形核白细胞（PMN）募集到肺中，从而导致IRI。 我们假设环核苷酸在维持内皮细胞骨架完整性方面起关键作用，而内皮细胞骨架完整性又在CAM上调中起作用。 该提案旨在：1）表征在循环停止之后但在再灌注之前的常温缺血期间在NHBD肺中发生的事件。2)测定停循环后IRI肺组织cAMP和cGMP与肺内皮通透性变化的关系。3)确定从NHBDs移植的肺中CAM表达、PMN募集和肺功能之间的关系。利用大鼠离体肺灌注模型和大鼠LTX模型，本建议旨在更好地理解IRI中涉及的分子事件，并制定策略，最大限度地减少从NHBDs中检索的肺损伤。这将有助于从NHBDs中引入肺移植，这有可能延长数千名患有各种肺部疾病的美国人的生命。

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.