COX-2 Mediated Inflammation of Cerebral Blood Vessels

COX-2介导的脑血管炎症

• 批准号: 6529750
• 负责人: JOHNNY E BRIAN
• 金额: $ 29.4万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529750
• 关键词: arachidonate; arterioles; bradykinin; cardiovascular pharmacology; cerebrovascular system; confocal scanning microscopy; enzyme activity; enzyme induction /repression; free radical oxygen; hydrogen peroxide; immunocytochemistry; inflammation; laboratory rat; neuroimmunomodulation; nitric oxide synthase; prostaglandin endoperoxide synthase; vasculitis; vasodilatation; vasodilation

DESCRIPTION (provided by the applicant): The overall goal of this application is to provide new insight into changes in the regulation of brain vascular tone following brain injury. Specifically, the proposed studies will investigate the mechanisms that subserve the delayed dilatation of brain arterioles that occurs after transient exposure to the acute vasodilators bradykinin or arachidonic acid. In brain, both bradykinin and arachidonic acid produce acute, reversible vasodilatation mediated by reactive oxygen species, most likely hydrogen peroxide. Reactive oxygen species have been shown in isolated tissues and cells to cause expression of cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase. We hypothesize that transient exposure of brain to bradykinin or arachidonic acid produces a delayed vasodilatation that occurs hours later. We also hypothesize that this delayed vasodilatation is mediated almost exclusively by COX-2, whose expression is upregulated by reactive oxygen species. The studies proposed in this application will use a cranial window model in anesthetized rats. Cranial windows offer the unique ability to study the cerebral circulation where it remains integrated brain tissue. Initial studies will undertake a systematic exploration of the concentration- and time-dependence of the delayed dilatation produced by acute exposure to bradykinin or arachidonic acid. Subsequent studies will use pharmacologic antagonists to establish the role of COX-2 and inducible NO-synthase in the delayed vasodilatation. Immunohistochemical studies will verify the expression of COX-2 protein and also identify the cell type expressing COX-2 by use of double labeling with confocal microscopy. The final series of projects will investigate the role of reactive oxygen species in bradykinin- and arachidonic acid-mediated delayed expression of COX-2. The specific role of hydrogen peroxide will be investigated, as well as the ability of hydrogen peroxide alone to induce delayed, COX-2 dependent dilatation. These studies will introduce an important new concept in the cerebral circulation - that acute dilators such as bradykinin and arachidonic acid can cause changes in gene expression that underlie delayed vascular effects.

描述（由申请人提供）：本申请的总体目标 是为脑血管张力调节的变化提供新的见解 脑损伤后。具体来说，拟议的研究将调查 促进脑小动脉延迟扩张的机制 短暂接触急性血管扩张剂缓激肽或花生四烯酸后 酸。在大脑中，缓激肽和花生四烯酸都会产生急性、可逆的 由活性氧（最有可能是氢）介导的血管舒张 过氧化物。分离的组织和细胞中已显示出活性氧 引起环氧合酶-2 (COX-2) 的表达，COX-2 是一种可诱导的异构体 环氧合酶。我们假设大脑短暂暴露于缓激肽 或花生四烯酸产生数小时后发生的延迟血管舒张。 我们还假设这种延迟的血管舒张几乎是由 完全由 COX-2 控制，其表达受活性氧上调 物种。本申请中提出的研究将使用颅窗 麻醉大鼠模型。颅窗提供独特的研究能力 脑循环，它仍然是完整的脑组织。最初的 研究将对集中度和 急性暴露所产生的延迟扩张的时间依赖性 缓激肽或花生四烯酸。后续研究将利用药理学 拮抗剂以确定 COX-2 和诱导型 NO 合酶在 延迟血管舒张。免疫组织化学研究将验证表达 COX-2 蛋白，并通过使用鉴定表达 COX-2 的细胞类型 共焦显微镜双标记。最终的一系列项目将 研究活性氧在缓激肽和花生四烯酸中的作用 酸介导的 COX-2 延迟表达。氢气的具体作用 将研究过氧化物以及过氧化氢的能力 单独诱导延迟的 COX-2 依赖性扩张。 这些研究将在大脑中引入一个重要的新概念 循环 - 缓激肽和花生四烯酸等急性扩张剂可以 引起延迟血管效应背后的基因表达变化。