Mechanisms of lung-dependent neutrophil priming in global cerebral ischemia-reperfusion injury

 描述(由申请人提供)：据估计，每年有50万美国人受到心脏骤停的影响，只有不到25%的患者能在出院后存活下来，主要原因是巨大的中枢神经系统损伤。心脏骤停复苏后综合征(PCAS)包括组织缺血的损害效应和缺血再灌注损伤(IRI)的延迟效应。先天免疫反应的激活是复苏后观察到的延迟性微血管损伤、血管通透性增加和进行性组织损伤的主要媒介。特别是，阻断白细胞向中枢神经系统的募集显著降低了脑缺血后观察到的损伤程度。在这项研究中，我们研究了外周炎症在全脑缺血中的病理后果，重点研究了肺炎症、中性粒细胞激活和迟发性中枢神经系统损伤之间的关系。这些研究的基础是我们观察到，针对II型肺泡细胞的细胞外超氧化物歧化酶(EC-SOD)的表达可以钝化中性粒细胞进入缺血后大脑的运输，并提供显着的神经保护。在这个建议中，我们测试了这样的假设，即EC-SOD在肺内的表达通过减少损伤相关分子模式(DAMP)的产生以及内皮和PMN激活所需的TLR4激活水平来抑制IRI。成功地证明了肺-脑耦合通过影响中性粒细胞启动来调节迟发性脑损伤，这可能为心脏骤停后出现的患者提供新的治疗策略。

 DESCRIPTION (provided by applicant): Cardiac arrest affects an estimated 500,000 Americans annually, and fewer than 25% patients will survive to discharge due in large part to overwhelming CNS injury. The post-resuscitation syndrome following cardiac arrest (PCAS) encompasses the damaging effects of tissue ischemia and the delayed effects of ischemic reperfusion injury (IRI). Activation of the innate immune response is a prime mediator of the delayed microvascular damage, increased vascular permeability and progressive tissue damage observed after resuscitation. In particular, blocking leukocyte recruitment to the CNS significantly reduces the extent of brain injury observed after ischemic challenge. In this proposal we investigate the pathological consequences of peripheral inflammation on global cerebral ischemia, focusing on the relationship between lung inflammation, neutrophil priming and delayed CNS injury. These studies are based on our observation that expression of extracellular superoxide dismutase (EC-SOD) targeted to type II pneumocytes blunts neutrophil trafficking into the post-ischemic brain and confers marked neuroprotection. In this proposal we test the hypothesis that expression of EC-SOD within the lung inhibits IRI by reducing the production of damage associated molecular patterns (DAMPs) and levels of TLR4 activation required for endothelial and PMN activation. Successful demonstration that lung-brain coupling modulates delayed cerebral injury through effects on neutrophil priming may suggest new treatment strategies for patients presenting after cardiac arrest.