脑内肥大细胞通过血管周隙明胶酶激活介导急性实验性缺血性卒中的血脑屏障破坏。
Cerebral mast cells mediate blood-brain barrier disruption in acute experimental ischemic stroke through perivascular gelatinase activation.
机构信息
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, and Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 8, 00029 Helsinki, Finland.
出版信息
Stroke. 2011 Dec;42(12):3600-5. doi: 10.1161/STROKEAHA.111.632224. Epub 2011 Oct 6.
BACKGROUND AND PURPOSE
Perivascularly positioned cerebral mast cells (MC) have been shown to participate in acute blood-brain barrier disruption and expansive brain edema following experimental transient cerebral ischemia. However, the underlying molecular mechanisms remain unknown. Because proteolytic gelatinase enzymes, matrix metalloproteinases (MMP)-2 and MMP-9, are thought to have a central role in compromising the integrity of the blood-brain barrier following ischemia, we examined whether cerebral MCs influence gelatinase activity in ischemic cerebral microvasculature.
METHODS
Rats underwent 60 minutes of middle cerebral artery occlusion followed by 3-hour reperfusion, and were treated with a MC-stabilizing (cromoglycate), or MC-degranulating (compound 48/80) agent, or vehicle. Genetically manipulated, MC-deficient WsRc(Ws/Ws) rats and their wild-type littermates (WT) underwent the same procedures. Cerebral edema and extravasation of Evans blue albumin were measured. Gelatinase activity was visualized by in situ zymography and was quantified with computerized high-throughput image and data analysis.
RESULTS
Activated MCs showed secretion of gelatinase-positive granules. Genetic MC deficiency decreased global gelatinase-active area (-69%, compared with WT; P<0.001) and the mean gelatinase activity of the ischemic microvasculature (-57% compared with WT; P=0.002). MC stabilization with cromoglycate decreased the percentage of microvessels with high gelatinase activity (-36% compared with saline; P<0.05). Compound 48/80 showed increased area of in situ zymography activity in the ischemic lesion (+55% compared with saline; P<0.001). Microvascular gelatinase activity correlated with brain swelling (r=0.84; P<0.001; and r=0.61; P=0.02).
CONCLUSIONS
Our data demonstrate that cerebral MCs participate in regulation of acute microvascular gelatinase activation and consequent blood-brain barrier disruption following transient cerebral ischemia.
背景与目的
研究表明，血管周定位的脑肥大细胞（MC）参与了实验性短暂性脑缺血后急性血脑屏障破坏和扩张性脑水肿。然而，其潜在的分子机制尚不清楚。由于蛋白水解酶明胶酶，基质金属蛋白酶（MMP）-2 和 MMP-9，被认为在缺血后破坏血脑屏障的完整性方面发挥着核心作用，我们研究了脑 MC 是否影响缺血性脑微血管中的明胶酶活性。
方法
大鼠进行 60 分钟大脑中动脉闭塞，然后再进行 3 小时再灌注，并给予 MC 稳定（色甘酸）或 MC 脱颗粒（化合物 48/80）药物或载体处理。遗传修饰的 MC 缺陷型 WsRc（Ws/Ws）大鼠及其野生型同窝仔鼠（WT）进行相同的处理。测量脑水肿和 Evans 蓝白蛋白外渗。通过原位酶谱法观察明胶酶活性，并通过计算机高通量图像和数据分析进行定量。
结果
活化的 MC 显示分泌明胶酶阳性颗粒。基因 MC 缺陷减少了整体明胶酶活性区域（与 WT 相比减少 69%；P<0.001）和缺血性微血管的平均明胶酶活性（与 WT 相比减少 57%；P=0.002）。色甘酸稳定 MC 减少了高明胶酶活性的微血管比例（与盐水相比减少 36%；P<0.05）。化合物 48/80 显示缺血性病变中的原位酶谱活性增加（与盐水相比增加 55%；P<0.001）。微血管明胶酶活性与脑水肿相关（r=0.84；P<0.001；r=0.61；P=0.02）。
结论
我们的数据表明，脑 MC 参与调节短暂性脑缺血后急性微血管明胶酶激活和随后的血脑屏障破坏。
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