Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia.
Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia.
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DOI：
10.1111/j.1471-4159.2008.05821.x
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发表时间：
2009-02
影响因子：
4.7
通讯作者：
Liu KJ
中科院分区：
文献类型：
--
作者：
Liu W;Hendren J;Qin XJ;Shen J;Liu KJ
由基质金属蛋白酶（MMPs）过度水解神经血管蛋白引起的早期血脑屏障（BBB）破坏与缺血性卒中的出血性转化事件密切相关。我们已经表明，常压高氧（NBO）治疗减少缺血性脑中MMP-9的增加。本研究的目的是确定NBO是否可以减弱缺血性卒中后MMP-9介导的早期BBB破坏。大鼠暴露于NBO（95%O2）或常氧（30%O2）在90分钟的大脑中动脉闭塞，随后3小时的再灌注。与常氧大鼠相比，NBO治疗大鼠缺血半球中的伊文思蓝外渗显着减少。从地形学上看，伊文思蓝渗漏主要见于包括纹状体在内的皮质下区域，伴随着明胶溶解活性增加和紧密连接蛋白occludin免疫染色减少。在离体缺血微血管中也观察到明胶分解活性增加和occludin蛋白丢失。凝胶明胶酶谱法证实MMP-9是脑微血管中的主要酶源。用纯化的MMP-9孵育脑切片或分离的微血管，揭示了occludin的特异性降解。通过NBO或MMP抑制剂BB 1101抑制MMP-9可显著减少缺血微血管中occludin蛋白的丢失。这些结果表明，NBO减弱早期血脑屏障破坏，抑制MMP-9介导的occludin降解是这种保护的重要机制。
Early blood-brain barrier (BBB) disruption, resulting from excessive neurovascular proteolysis by matrix metalloproteinases (MMPs), is closely associated with hemorrhagic transformation events in ischemic stroke. We have shown that normobaric hyperoxia (NBO) treatment reduces MMP-9 increase in the ischemic brain. The aim of this study was to determine whether NBO could attenuate MMP-9-mediated early BBB disruption following ischemic stroke. Rats were exposed to NBO (95% O2) or normoxia (30% O2) during 90-min middle cerebral artery occlusion, followed by 3-hr reperfusion. NBO-treated rats showed significant reduction in Evan’s blue extravasation in the ischemic hemisphere compared with normoxic rats. Topographically, Evan’s blue leakage was mainly seen in the subcortical regions including striatum, which was accompanied by increased gelatinolytic activity and reduced immunostaining for tight junction protein occludin. Increased gelatinolytic activities and occludin protein loss were also observed in isolated ischemic microvessels. Gel gelatin zymography identified that MMP-9 was the main enzymatic source in the cerebral microvessels. Incubation of brain slices or isolated microvessels with purified MMP-9 revealed specific degradation of occludin. Inhibition of MMP-9 by NBO or MMP-inhibitor BB1101 significantly reduced occludin protein loss in ischemic microvessels. These results suggest that NBO attenuates early BBB disruption, and inhibition of MMP-9-mediated occludin degradation is an important mechanism for this protection.
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影响因子：
8.2
作者：
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