Vascular Protection in Acute Ischemic Stroke

描述(由申请人提供)：再灌注疗法使闭塞的大脑动脉重新开放是缺血性中风患者完全康复的最好机会。尽管如此，在每年60多万名患者中，接受这种疗法的不到5%。广泛使用的主要障碍之一是担心严重脑出血的风险增加10倍，这可能是致命的。迫切需要制定战略来降低这种风险。很明显，缺血损害脑血管，在某些情况下，这会导致脑出血。这项研究的目的是确定脑再灌注后出血的原因，并评估在实验性中风模型中提供血管保护的方法。我们假设组织衍生基质金属蛋白酶(MMPs)和血液中性粒细胞在血管损伤中都是必需的，血管损伤导致出血，有时还会恶化预后。我们计划通过调查以下两个具体目标来验证这一假说：1)确定中性粒细胞和组织MMPs在短暂性脑缺血后脑微血管完整性破坏中的作用。2)评价血管保护策略对短暂性脑缺血的治疗效果。这些特定的目标将通过使用再灌注出血的大鼠模型来实现，在该模型中，将严格评估中性粒细胞耗尽、基质金属蛋白酶抑制、基质金属蛋白酶酶谱和对比增强磁共振成像(MRI)，以评估出血发生过程中的致病机制。总共将在三年内对189只动物进行研究。在完成上述实验后，我们希望充分了解中性粒细胞和组织衍生基质蛋白酶在脑血管破坏中的相对作用，以及可能具有血管保护作用并有助于改善结果的策略。总而言之，本提案中总结的研究的成功完成有望有助于开发使再灌注更安全的方法，从而使人类中风患者更容易获得再灌注。

DESCRIPTION (provided by applicant): Reperfusion therapy to reopen an occluded cerebral artery is the best chance that ischemic stroke patients have of making a full recovery. Despite this less than 5% of the more than 600,000 annual patients receive the therapy. One of the main barriers to the wide spread use is the fear of the 10X increase risk of severe brain hemorrhage, which can be fatal. There is an urgent need to develop strategies to reduce this risk. It is clear that ischemia damages brain blood vessels and, in some cases, this leads to brain hemorrhage. The objective of this research is to determine why the brain bleeds upon reperfusion and to evaluate ways to provide vascular protection in an experimental stroke model. We hypothesize that both tissue-derived matrix metalloproteinases (MMPs) and blood neutrophils are necessary for the blood vessel damage that leads to hemorrhage and sometimes, worsened outcome. We plan to test this hypothesis by investigating the following two specific aims: 1) Determine the contribution of neutrophils and tissue MMPs to the disruption of microvascular integrity in the brain following temporary cerebral ischemia. 2) Evaluate the therapeutic efficacy of vascular protection strategies for temporary cerebral ischemia. These specific aims will be achieved using a rat model of reperfusion hemorrhage in which neutrophil depletion, MMP inhibition, MMP zymography and contrast-enhanced magnetic resonance imaging (MRI) will be critically evaluated to assess pathogenic mechanisms operative in the development of hemorrhage. A total of 189 animals will be studied over a three year period. At the completion of the above experiments, we expect to have a full understanding of the relative contributions of neutrophils and tissue-derived matrix proteases to the destruction of the cerebral blood vessel and the strategies that are likely to be vascular protective and contribute to improved outcome. Collectively, the successful completion of the research summarized in this proposal can be expected to contribute to the development of methods to make reperfusion safer, and therefore more accessible, to human stroke patients.