Microvascular injury after Subarachnoid Hemorrhage

蛛网膜下腔出血后微血管损伤

基本信息

批准号：
7470641
负责人：
FATIMA A SEHBA
金额：
$ 29.66万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470641
关键词：
Accounting Acute Acute Brain Injuries Affect Aneurysmal Subarachnoid Hemorrhages Angiography Animal Behavior Animals Apoptosis Aspirin Attention Basal Lamina Collagen Basal lamina Behavior Blood Blood - brain barrier anatomy Blood Platelets Blood Pressure Blood Vessels Blood flow Brain Brain Injuries Cause of Death Cerebral Ischemia Cerebrovascular Circulation Cerebrum Cessation of life Collagen Type IV Constriction procedure Data Development Disruption Electron Microscopy Elements Endothelial Cells Endothelium Event Experimental Designs Experimental Models Extravasation Fibrin Foundations Gelatinase B Grooming Hemorrhage Horseradish Peroxidase Hour Human Image Immunofluorescence Immunologic Impairment Injection of therapeutic agent Injury Intracranial Aneurysm Intracranial Pressure Ischemia Laser-Doppler Flowmetry Matrix Metalloproteinases Measures Microtomy Microvascular Permeability Nature Nervous System Physiology Neurologic Examination Neurological outcome Neurological status Neurophysiology - biologic function Outcome Patients Perforation Perfusion Personal Satisfaction Pharmaceutical Preparations Pharmacological Treatment Platelet Aggregation Inhibition Platelet aggregation Proteins Rattus Recovery Research Design Resolution Role Ruptured Aneurysm SB 3CT compound Saline Serum Proteins Signal Transduction Site Source Spasm Specimen Staining method Stains Stroke Structural Protein Structure Subarachnoid Hemorrhage Subarachnoid Space Testing Therapeutic Time Tracer Travel blood perfusion collagenase day design disability feeding foot improved inhibitor/antagonist prevent rat endothelial barrier antigen research study therapy design therapy outcome time interval

项目摘要

DESCRIPTION (provided by applicant): Aneurysmal subarachnoid hemorrhage (SAH) accounts for 5-10% of annual stroke cases. 50% of the patients die within 30 days with most deaths occurring within the first 48 hours. Acute brain injury after SAH is ischemic in nature and develops within the first 48 hours with mechanisms that are poorly understood. No effective treatment for it currently exists. We have found structural injury in cerebral microvessels after SAH that could affect their function and contribute to acute ischemia. This study investigates the effect of structural injury on microvessel function and the role of intraluminal platelet aggregation in initiating these events after SAH. In an experimental model of SAH we have found intraluminal platelet aggregation, degradation of collagen IV, the major protein of basal lamina, and activation of vascular collagenases within hours after SAH. This study will test the hypotheses that platelet aggregation: 1. reduces microvascular perfusion and 2. initiates the destruction of perivascular collagen IV and thereby causes local breaches of the blood-brain barrier. SAH will be induced in the rat by endovascular perforation. Cerebral blood flow, blood pressure and intracranial pressure will be continuously recorded. Cerebral microvessels (slOOum) will be examined for perfusion, blood-brain barrier function, platelet aggregation, endothelial injury, matrix metalloproteinase-9 activation, and collagen IV loss during the first 48 hours after SAH. The effect of early pharmacological inhibition of platelet aggregation on microvascular perfusion and structural changes will be investigated. Animal behavior and neurological status will be examined to establish the outcome of this therapy on neural function. The experimental design will focus on four major questions: 1) what is the effect of intraluminal platelet aggregation on microvascular perfusion after SAH?, 2) do intraluminal platelet aggregates act as initiators of basal lamina degradation and blood brain barrier disruption after SAH?, 3) what fine structural changes occur in the microvasculature after SAH?, and 4) does early pharmacological inhibition of platelet aggregation improve neurological outcome? This study will extend our current understanding of early microvascular injury after SAH, and will evaluate the therapeutic potential of post-hemorrhage blockade of platelet aggregation.

描述（由申请人提供）：动脉瘤性蛛网膜下腔出血 (SAH) 占每年中风病例的 5-10%。 50% 的患者在 30 天内死亡，其中大多数死亡发生在最初的 48 小时内。 SAH 后的急性脑损伤本质上是缺血性的，并在最初的 48 小时内发生，其机制尚不清楚。目前尚无有效的治疗方法。我们发现蛛网膜下腔出血后脑微血管的结构损伤可能会影响其功能并导致急性缺血。本研究探讨了结构损伤对微血管功能的影响以及 SAH 后腔内血小板聚集在引发这些事件中的作用。在 SAH 的实验模型中，我们发现 SAH 后数小时内腔内血小板聚集、基底层主要蛋白质 IV 型胶原蛋白降解以及血管胶原酶激活。这项研究将检验以下假设：血小板聚集：1. 减少微血管灌注；2. 引发血管周围 IV 型胶原蛋白的破坏，从而导致血脑屏障局部破裂。血管内穿孔将在大鼠中诱发SAH。脑血流量、血压和颅内压将被连续记录。在SAH后的前48小时期间将检查脑微血管(s100um)的灌注、血脑屏障功能、血小板聚集、内皮损伤、基质金属蛋白酶9激活和胶原IV损失。将研究早期药物抑制血小板聚集对微血管灌注和结构变化的影响。将检查动物行为和神经状态以确定该疗法对神经功能的结果。实验设计将重点关注四个主要问题：1) 腔内血小板聚集对 SAH 后微血管灌注有何影响？2) 腔内血小板聚集是否会成为 SAH 后基底层降解和血脑屏障破坏的引发剂？ 3 ) SAH 后微血管系统发生了哪些精细结构变化？以及 4) 早期药物抑制血小板聚集是否可以改善神经系统结果？这项研究将扩展我们目前对 SAH 后早期微血管损伤的理解，并将评估出血后血小板聚集阻断的治疗潜力。