ISCHEMIC INJURY IN CADAVER DONORS FOR LUNG TRANSPLANT

临床肺移植(LTX)因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在等待LTX的过程中死亡，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。肺在固体器官中是独一无二的，因为它不依赖于细胞呼吸的灌流。我们假设肺组织在循环停止和死亡后仍能存活数小时，因此肺可能适合移植，即使在循环停止和非心脏跳动器官供者死亡(NHBD)后相当长的时间间隔被取回。我们已经用动物LTX实验证实了这一假说，这些实验表明，在循环停止后每隔一段时间取回的肺可能功能良好，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是肺缺血再灌注损伤时内皮细胞通透性改变的重要介质。IRI与内皮细胞黏附分子(CAM)表达上调有关，内皮细胞黏附分子将中性粒细胞(PMN)募集到肺内，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发挥关键作用，而内皮细胞骨架完整性反过来又在CAM上调中发挥作用。这项建议的目的是：1)描述常温缺血期NHBD肺循环停止后再灌流前发生的事件。2)探讨停循环后肺组织cAMP、cGMP与肺内皮细胞通透性变化的关系。3)研究NHBD移植肺中细胞间黏附分子的表达、PMN募集与肺功能的关系。利用大鼠离体肺灌流模型和大鼠LTX模型，该建议旨在更好地了解IRI所涉及的分子事件，并开发在从NHBD检索的背景下将肺损伤降至最低的策略。这将促进从NHBD中移植肺的引入，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.