The role of neutrophils in SAH

描述（由申请人提供）：蛛网膜下腔出血是美国卒中的第三大原因，但占脑血管事件死亡率和发病率的50%。迟发性脑缺血综合征（血管痉挛）是蛛网膜下腔出血的一种常见、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未阐明。中性粒细胞产生活性氧化物（ROS）。ROS参与血管痉挛的发病机制，并被认为有助于氧化损伤和一氧化氮（NO）耗竭。这些被认为有助于血管痉挛中的血管功能障碍。我们建议测试的假设，中性粒细胞聚集在蛛网膜下腔和选择性增加嗜中性粒细胞衍生的氧化途径的分子标志物将与蛛网膜下腔出血后血管痉挛的发生。我们计划通过发展两个具体目标来研究这一点：1）我们将建立蛛网膜下腔中性粒细胞富集、不同氧化途径的稳定分子标记物和血管痉挛之间的关系;和2）我们将确定中性粒细胞耗竭、活化、两种中性粒细胞酶NADPH氧化酶和MPO失活的含义，以及趋化因子CXCR 2在鼠模型中对血管痉挛发展的失活。血管痉挛没有有效的治疗方法。这一建议将导致更好地理解的途径，中性粒细胞浸润和行动可能导致血管痉挛。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。这个建议和教育组成部分包括形式的基础上，博士Provencio发展成为一个独立的医生，科学家。

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.