Role of lung-brain coupling on neutrophil priming and reperfusion injury following global cerebral ischemia

 描述(由申请人提供)：心脏骤停后的神经康复伴有一系列器官功能障碍和全身炎症，称为心脏骤停后综合征(PCAS)。在自主循环恢复后，脑再灌注伴随着神经毒性中性粒细胞(PMN)的迁移，这些PMN会导致血脑屏障功能障碍和局部组织损伤，释放降解酶、细胞因子和活性氧物种。最近在肺和重症监护领域的工作表明，启动是可逆的，并在PMN-肺内皮细胞界面上介导。我们的实验室已经发现，肺组织中靶向表达细胞外超氧化物歧化酶(SOD3，一种抗氧化酶)可以改变PMN的动力学和缺血再灌注后神经元的损伤。在这项建议中，我们在一种结合了全脑缺血-再灌注和全身炎症效应的PCAS小鼠模型中，研究了肺部炎症、PMN激活和脑缺血-再灌注损伤之间的联系。我们假设PCAS诱导PMN启动，肺中SOD3活性和炎症水平反过来调节它们在穿过缺血后脑血管时的组织毒性效应。这些实验将测试操纵SOD3活性的影响：1)PMN的时空转运和对中枢神经系统的缺血损伤程度；2)PMN的体外神经毒性；3)肺是否能有效地使暴露于体外启动刺激的PMN“去激活”并通过输血重新进入体循环。这些研究强调了肺-脑耦合在缺血再灌注损伤中的潜在作用，并将重点放在PMN启动回路作为治疗干预的潜在靶点上。鉴于肺在调节缺血-再灌注损伤的炎症反应中的显著作用，肺是一个容易获得的靶点，可以在其中测试假定的神经保护策略。

 DESCRIPTION (provided by applicant): Neurologic recovery after cardiac arrest is complicated by a constellation of organ dysfunction and systemic inflammation known as Post Cardiac Arrest Syndrome (PCAS). After return of spontaneous circulation, reperfusion of the brain is accompanied by the migration of "primed," neurotoxic neutrophils (PMNs) that cause blood-brain-barrier dysfunction and damage to local tissue with the release of degradative enzymes, cytokines, and reactive oxygen species. Recent work in the fields of pulmonary and critical care suggests that priming is reversible and mediated at the PMN-pulmonary endothelium interface. Our lab has found that targeted expression of extracellular superoxide dismutase (SOD3, an antioxidant enzyme) in the lung alters PMN kinetics and neuronal injury after ischemia-reperfusion. In this proposal we investigate the link between lung inflammation, PMN activation, and cerebral ischemia-reperfusion injury in a mouse model of PCAS that combines the effects of global cerebral ischemia-reperfusion and systemic inflammation. We hypothesize that PCAS induces PMN priming, and that the level of SOD3 activity and inflammation in the lung in turn modulates their histotoxic effects of as they traverse the post-ischemic cerebrovasculature. The experiments proposed will test the effects of manipulating SOD3 activity on: 1) the spatiotemporal trafficking of PMNs and degree of ischemic injury to the CNS observed, 2) PMN neurotoxicity in vitro, and 3) whether the lung can effectively "de-prime" PMNs exposed to priming stimuli ex vivo and reintroduced to the systemic circulation by transfusion. These studies highlight the potential role of lung-brain coupling in ischemia-reperfusion injury and focus on the PMN priming circuit as a potential target for therapeutic intervention. Given its salient role in modulating the inflammatory response to ischemia-reperfusion injury, the lung is an easily accessible target in which putative neuroprotective strategies may be tested.