REPERFUSION IN EXPERIMENTAL BRAIN INFARCT

本提案的总体目标是：（l）确定结构 由动脉闭塞引起的脑内变化，以及（2）检查 再灌注对“进化性局灶性脑梗死”的贡献 缺血”可能对减少由缺血引起的组织学损伤 动脉闭塞或诱发出血性并发症。 “不断发展 局部缺血”描述了一系列结构异常， 动脉阻塞引起的运动。 所适用的程序允许 闭塞并重新打开大脑中动脉（MCA），而不打开 颅骨;这被认为是必要的，以维持颅内压 除了局部脑缺血外没有受到任何影响 评估方法 组织改变包括体内核磁共振成像 (MRI)以及大脑微血管的详细显微镜检查， 神经元/星形胶质细胞成分以确定：（a）微血管的开放性， (b)血脑屏障对大分子的完整性，（c）时机和 红细胞堵塞微血管的地形分布， 纤维蛋白、血小板或这些的组合，（d）最早到达， 多形核白细胞的内皮沉积，和（e）定义 实质变化的证据 这些变化将被评估为 载瘤动脉闭塞后消失的功能和程度， 损伤类型的神经元/星形胶质细胞位于领土的 闭塞动脉 早期脑梗塞的自发性出血 这并不是一种罕见的并发症，但是， 对这一事件了解甚少（6，42）。两个一般假设是 测试：（1）由动脉闭塞引发的脑损伤演变为 通过两个阶段：急性缺血性损伤在几分钟内开始， 随后是延迟的变化（或梗死）;这两个阶段是分开的 彼此之间的距离，至今还没有确定的时间;（2） 急性缺血期缺血区的再灌注 损伤将改善组织学异常，而再灌注 在延迟变化期间，将导致脑内 出血机制假说：出血，作为大脑的并发症 梗塞是广泛的内皮坏死的结果（影响 微血管系统）;增加出血期间的因素 微血管坏死包括再灌注。 丰富的存在 局灶性缺血区域的中性粒细胞有助于内皮细胞 坏死（52，92），因此诱发脑出血。 在 鉴于目前对发展“缺血性”疾病的快速治疗的兴趣， 血栓溶解剂联合狭窄动脉内膜切除术治疗“中风” 动脉，这些实验的结果可能会产生重大影响， 急性缺血性中风的未来管理。

The overall objectives of this proposal are to (l) define the structural changes initiated in the brain by an arterial occlusion, and (2) examine the contribution that reperfusing an area of "evolving focal cerebral ischemia" may have on either decreasing the histologic damage initiated by the arterial occlusion or inducing hemorrhagic complications. "Evolving focal ischemia" describes the series of structural abnormalities set in motion by an arterial occlusion. The procedures to be applied allow to occlude and re-open a middle cerebral artery (MCA) without opening the skull; this is deemed essential in order to maintain intracranial pressure unaffected by anything but focal brain ischemia. The methods to evaluate the tissue alterations include in-vivo Nuclear Magnetic Resonance Imaging (MRI) and detailed microscopy of the cerebral microvasculature and neuronal/astrocytic components to determine: (a) patency of microvessels, (b) integrity of the blood-brain barrier to macromolecules, (c) timing and topographic distribution of microvascular plugging by red blood cells, fibrin, platelets, or combinations of these, (d) earliest arrival and endothelial apposition of polymorphonuclear leukocytes, and (e) definition of the parenchymal changes. These alterations will be evaluated as a function of the elapsed after occluding the parent artery and degree or type of injury to the neurons/astrocytes located in the territory of the occluded artery. Spontaneous bleeding into an incipient brain infarct is not an uncommon complication but, the mechanisms and, the prevention of this event are poorly understood(6,42). Two general hypotheses will be tested: (1) The brain lesion initiated by an arterial occlusion evolves through two stages: acute ischemic injury begins within minutes and is followed by delayed changes (or infarct); these two stages are separated from one another by an as yet undetermined number of hours; (2) Reperfusing the ischemic territory during the period of acute ischemic injury will improve the histologic abnormalities, whereas reperfusion during the period of delayed changes will result in intracerebral hemorrhage. Mechanistic hypothesis: Bleeding, as a complication of a brain infarct, is a consequence of widespread endothelial necrosis (affecting the microvasculature); factors that enhance bleeding during the period of microvascular necrosis include reperfusion. The presence of abundant neutrophils in the area of focal ischemia contributes to the endothelial necrosis(52,92) and therefore to the induction of brain hemorrhage. In view of the current interest in developing prompt treatment of "ischemic stroke" with both thrombolytic agents and endarterectomy of stenotic arteries, the results of these experiments may have significant impact in the future management of acute ischemic stroke.