The role of neutrophils in SAH

中性粒细胞在 SAH 中的作用

• 批准号: 7739492
• 负责人: Jose Javier Provencio
• 金额: $ 16.97万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-02 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739492
• 关键词: Accounting; Address; Admission activity; Aneurysmal Subarachnoid Hemorrhages; Astrocytes; Biological Assay; Blood; Blood Circulation; Blood Vessels; Blood donor; Blood specimen; Brain; CXCL1 gene; Cerebral Aneurysm; Cerebral Ischemia; Cerebrospinal Fluid; Cerebrovascular Spasm; Cerebrum; Clinical; Collection; Complex; Complication; Development; Disease; Doctor of Medicine; Dose; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Enzymes; Event; Experimental Models; Flow Cytometry; Functional disorder; Generations; Goals; Head; Hemorrhage; Human; Hydroxyl Radical; IL8 gene; IL8RB gene; Imaging Techniques; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knockout Mice; Knowledge; Lead; Lipids; Liquid substance; Mass Spectrum Analysis; Mediating; Modeling; Monitor; Morbidity - disease rate; Mus; NADPH Oxidase; Neurologic; Neutrophil Activation; Neutrophil Infiltration; Nitrates; Nitric Oxide; Nitrites; Nucleic Acids; Oxidants; Pathogenesis; Pathway interactions; Patients; Pattern; Peroxidases; Phenylalanine; Physicians; Physiology; Post-Translational Protein Processing; Production; Proteins; Recruitment Activity; Relative (related person); Reporting; Research Personnel; Research Training; Risk; Role; Rupture; Sampling; Scientist; Severities; Source; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Superoxides; Syndrome; Testing; Therapeutic; Time; Tissues; Tyrosine; United States; Vascular Endothelial Cell; Vasospasm; Wild Type Mouse; base; career; chemokine; chemokine receptor; cohort; disability; effective therapy; inflammatory marker; information gathering; insight; molecular marker; mortality; mouse model; neutrophil; prevent; programs; research study; tool; vasoconstriction

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.

蛛网膜下腔出血是美国中风的第三大原因，但占50% 脑血管事件中死亡率和发病率的百分比。延迟性脑损伤综合征 脑缺血(血管痉挛)是蛛网膜下腔常见、危险且知之甚少的并发症。 大出血。蛛网膜下腔早期炎症反应以中性粒细胞浸润为主 然而，中性粒细胞及其产物在介导血管痉挛中的作用尚未得到证实。 已澄清。中性粒细胞产生活性氧化剂(ROS)。ROS与糖尿病的发病机制有关。 血管痉挛，被认为是导致氧化损伤和一氧化氮(NO)耗竭的原因。这些是 据信与血管痉挛时的血管功能障碍有关。我们建议对假设进行检验 蛛网膜下腔中性粒细胞聚集与中性粒细胞衍生分子的选择性增加 氧化途径标记物与蛛网膜下腔血管痉挛的发生相关 大出血。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增多与稳定分子标志物的关系 氧化途径和血管痉挛；以及2)我们将确定中性粒细胞耗尽的含义， NADPH氧化酶和MPO两种中性粒细胞酶的失活，以及 趋化因子CXCR2在小鼠血管痉挛发展中的作用。没有有效的治疗方法 血管痉挛的症状。这一提议将使人们更好地理解中性粒细胞 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潜在药物治疗靶点。这项建议 所包含的教育成分构成了普罗文西奥博士发展成为独立的 医生兼科学家。