EICOSANOID METABOLISM AT THE BLOOD-BRAIN BARRIER

越来越多的长链、多不饱和烃的含氧衍生物 脂肪酸在大脑中被描述。 其中包括 化合物是洋地黄素、羟基二十碳四烯酸（HETE）和 白三烯 尽管许多类花生酸介导良好- 以其他组织中的生理或病理生理事件为特征， 他们在大脑的生物过程中的作用，特别是， 脑血管相对来说是未知的。 一些功能具有 从控制脑血管紧张度到采取行动， 作为递质物质或细胞内第二信使， 中风、脑外伤和癫痫的病理生理事件。 我们和其他人以前已经确定了几种代谢物或花生四烯酸 离体脑微血管产生的二十碳五烯酸 微血管内皮细胞的制备和纯化培养 和平滑肌细胞。 然而，通过产生类花生酸， 微血管细胞，其生产的调节， 这些花生四烯酸衍生物对大脑的功能作用 循环和邻近脑实质保留不完全 表征了 对代谢和功能的了解更少， 大脑循环细胞中的ω-3脂肪酸。 因此 为了更全面地理解， 脑内长链多不饱和脂肪酸生物学 微血管 首先，白三烯和HETE的代谢将被抑制。 在培养的脑内皮和分离的脑微血管中探索。 这些化合物在许多类型的脑损伤中产生， 潜在的病理生理介质。 第二，进行研究 为了鉴定ω-3脂肪酸的脑血管代谢物， 二十碳五烯酸和二十二碳六烯酸，这些脂肪酸可以防止 或改善脑血管疾病的病理。 三是 细胞间相互作用对类花生酸生物合成的调控 微血管壁的成分、星形胶质细胞、平滑肌细胞，以及 内皮细胞，将被检查。 脑内皮细胞的许多方面 分化是由星形胶质细胞和类似的 内皮和平滑肌之间可能存在关系。 在 此外，构成脑血管壁的细胞可以共享类二十烷酸， 前体或中间体。 最后，大脑的功能反应 微血管的具体类花生酸将研究利用 体内和体外软脑膜血管制备物和一种免疫抑制剂的组合 血脑屏障的体外模型。 类花生酸具有巨大的潜力 作为脑血管壁内的自分泌或旁分泌化合物 因此可能影响血管张力和血脑屏障特性。 这 体外和体内方法的组合是独特的，应证明 是了解大脑中类花生酸生物学的一个强有力的方法， 微循环

A growing number of oxygenated derivatives of long chain, polyunsaturated fatty acids are being described in the brain. Included among these compounds are prostaglandins, hydroxyeicosatetraenoic acids (HETEs), and leukotrienes. Although many of these eicosanoids mediate well- characterized physiological or pathophysiological events in other tissues, their role in the biological processes of the brain, and in particular, the cerebral blood vessels, is relatively unknown. A number functions have been proposed, ranging from the control of cerebrovascular tone, to action as transmitter substances or intracellular second messengers, to mediation of pathophysiologic events in stroke, brain trauma, and seizure. We and others have previously identified several metabolites or arachidonic acid and eicosapentaenoic acid produced by isolated brain microvessel preparations and by purified cultures of cerebromicrovascular endothelium and smooth muscle cells. Yet, the production of eicosanoids by cerebromicrovascular cells, the regulation of their production, and the function effects these arachidonic acid derivatives have on the cerebral circulation and adjacent brain parenchyma remain incompletely characterized. Even less is known about the metabolism and function of omega-3 fatty acids in cells of the cerebral circulation. Thus, the following aims are proposed in order to more completely understand the biology of long chain, polyunsaturated fatty acids in cerebral microvessels. First, the metabolism of leukotrienes and HETEs will be explored in cultured cerebral endothelium and isolated brain microvessels. These compounds are produced in many types of brain injury and are potential pathophysiologic mediators. Second, studies will be undertaken to identify the cerebrovascular metabolites of the omega-3 fatty acids, eicosapentaenic acid and docosahexaenoic acid, fatty acids that may prevent or ameliorate the pathology of cerebrovascular disease. Third, the regulation of eicosanoid biosynthesis by interactions among cellular components of the microvascular wall, astrocytes, smooth muscle cells, and endothelium, will be examined. Many aspects of cerebral endothelial differentiation are induced or modulated by astrocytes and similar relationships may exist between endothelium and smooth muscle. In addition, cells that comprise the cerebrovascular wall may share eicosanoid precursors or intermediates. Finally, the functional responses of cerebral microvessels to specific eicosanoids will be studied utilizing a combination of in vivo and in vitro pial vessel preparations and an in vitro model of the blood-brain barrier. Eicosanoids have great potential to act as autocrine or paracrine compounds within the cerebrovascular wall and may thus effect vascular tone and blood-brain barrier properties. This combination of in vitro and in vivo methods is unique and should prove to be a powerful approach to understanding eicosanoid biology in the cerebral microcirculation.