The role of neutrophils in SAH

描述(申请人提供)：蛛网膜下腔出血是美国中风的第三大原因，但占脑血管事件死亡率和发病率的50%。迟发性脑缺血(血管痉挛)综合征是蛛网膜下腔出血的常见、危险且知之甚少的并发症。中性粒细胞浸润是蛛网膜下腔出血的主要早期炎症反应；然而，中性粒细胞及其产物在介导血管痉挛中的作用尚不清楚。中性粒细胞产生活性氧化剂(ROS)。ROS与血管痉挛的发病机制有关，并被认为与氧化损伤和一氧化氮(NO)耗竭有关。这些被认为与血管痉挛时的血管功能障碍有关。我们建议验证这一假设，即蛛网膜下腔内中性粒细胞聚集和氧化途径中性粒细胞衍生的分子标志物选择性增加将与蛛网膜下腔出血后血管痉挛的发生相关。我们计划通过发展两个特定的目标来研究这一点：1)我们将建立不同氧化途径的稳定分子标记的中性粒细胞在蛛网膜下腔丰富与血管痉挛之间的关系；2)我们将在小鼠模型中确定中性粒细胞耗竭、激活、两种中性粒细胞酶NADPH氧化酶和MPO的失活以及趋化因子CXCR2的失活在血管痉挛发展中的意义。目前还没有有效的治疗血管痉挛的方法。这一建议将有助于更好地了解中性粒细胞渗透和作用可能导致血管痉挛的途径。这是相关的，因为中性粒细胞和中性粒细胞趋化因子是预防或治疗血管痉挛的药物治疗的潜在靶点。这项提议和其中包含的教育内容构成了普罗文西奥博士发展成为一名独立的内科科学家的基础。

DESCRIPTION (provided by applicant): Subarachnoid hemorrhage is the third leading cause of stroke in the United States but accounts for fifty percent of the mortality and morbidity in cerebral vascular events. The syndrome of delayed cerebral ischemia (vasospasm) is a common, dangerous and poorly understood complication of subarachnoid hemorrhage. Neutrophil infiltration is the predominant early inflammatory response in subarachnoid hemorrhage; however, the role of neutrophils and their products in mediating vasospasm has not been elucidated. Neutrophils make reactive oxidant species (ROS). ROS are implicated in the pathogenesis of vasospasm and are believed to contribute to oxidative injury and nitric oxide (NO) depletion. These are believed to contribute to the blood vessel dysfunction in vasospasm. We propose to test the hypothesis that neutrophil accumulation in the subarachnoid space and selective increase in neutrophil-derived molecular markers of oxidative pathways will correlate with the occurrence of vasospasm after subarachnoid hemorrhage. We plan to investigate this by developing two Specific Aims: 1) We will establish the relationship between neutrophil enrichment in the subarachnoid space, stable molecular markers of distinct oxidative pathways and vasospasm; and 2) we will determine the implications of neutrophil depletion, activation, the inactivation of two neutrophil enzymes, NADPH oxidase and MPO, and the inactivation of the chemokines CXCR2 on the development of vasospasm in a murine model. There is no effective treatment of vasospasm. This proposal will lead to a better understanding of the pathways by which neutrophil infiltration and action may lead to vasospasm. This is relevant because neutrophils and neutrophil chemokines are potential targets for pharmacologic therapy to prevent or treat vasospasm. This proposal and the educational components included form the basis for Dr. Provencio to develop into an independent physician-scientist.