The role of neutrophils in SAH

在美国，蛛网膜下腔出血是中风的第三大原因， 占脑血管事件死亡率和发病率的百分比。迟发性脑梗死综合征 缺血（血管痉挛）是一种常见的、危险的和知之甚少的蛛网膜下腔并发症 出血神经元浸润是蛛网膜下腔主要的早期炎症反应 出血;然而，中性粒细胞及其产物在介导血管痉挛中的作用尚未被证实。 阐明。中性粒细胞产生活性氧化物（ROS）。活性氧参与了 血管痉挛，并被认为有助于氧化损伤和一氧化氮（NO）消耗。这些是 被认为是导致血管痉挛的血管功能障碍的原因。我们提议验证这个假设 中性粒细胞在蛛网膜下腔的聚集和嗜中性粒细胞衍生分子的选择性增加 氧化途径的标志物将与蛛网膜下腔出血后血管痉挛的发生相关， 出血我们计划通过制定两个具体目标来调查这一点：1）我们将建立 蛛网膜下腔中性粒细胞富集、不同的中性粒细胞的稳定分子标志物 氧化途径和血管痉挛; 2）我们将确定中性粒细胞耗竭的影响， 激活，两种中性粒细胞酶，NADPH氧化酶和MPO的失活，以及 在小鼠模型中，趋化因子CXCR 2对血管痉挛发展的影响。尚无有效的治疗方法 血管痉挛这一建议将导致更好地理解的途径，中性粒细胞 渗透和作用可导致血管痉挛。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。这项建议 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 物理学家兼科学家

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 proposal to test the hypothesisthat 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.