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

 描述（由申请人提供）：心脏骤停后的神经恢复因一系列器官功能障碍和全身炎症而复杂化，称为心脏骤停后综合征（PCAS）。自发循环恢复后，脑的再灌注伴随着“致敏的”神经毒性嗜中性粒细胞（PMN）的迁移，其导致血脑屏障功能障碍和局部组织损伤，并释放降解酶、细胞因子和活性氧。最近在肺部和重症监护领域的工作表明，启动是可逆的，并在中性粒细胞-肺内皮界面介导。我们的实验室已经发现，靶向表达细胞外超氧化物歧化酶（SOD 3，一种抗氧化酶）在肺改变PMN动力学和缺血再灌注后的神经元损伤。在这个建议中，我们调查肺部炎症，中性粒细胞活化，脑缺血再灌注损伤的小鼠模型PCAS，结合全球脑缺血再灌注和全身炎症的影响之间的联系。我们假设PCAS诱导PMN启动，并且当它们穿过缺血后血管系统时，肺中的SOD 3活性和炎症水平反过来调节它们的组织毒性作用。所提出的实验将测试操纵SOD 3活性对以下的影响：1）观察到的PMN的时空运输和对CNS的缺血性损伤程度，2）体外PMN神经毒性，和3）肺是否可以有效地“去预充”暴露于预充刺激的PMN离体并通过输血重新引入体循环。这些研究强调了肺-脑偶联在缺血-再灌注损伤中的潜在作用，并将PMN启动回路作为治疗干预的潜在靶点。鉴于其在调节缺血再灌注损伤的炎症反应中的突出作用，肺是一个容易接近的靶点，其中可以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.