Cerebral Mast Cells Mediate Blood-Brain Barrier Disruption in Acute Experimental Ischemic Stroke Through Perivascular Gelatinase Activation
Cerebral Mast Cells Mediate Blood-Brain Barrier Disruption in Acute Experimental Ischemic Stroke Through Perivascular Gelatinase Activation
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DOI：
10.1161/strokeaha.111.632224
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发表时间：
2011-12-01
期刊：
影响因子：
8.3
通讯作者：
Lindsberg, Perttu J.
中科院分区：
文献类型：
--
作者：
Mattila, Olli S.;Strbian, Daniel;Lindsberg, Perttu J.
背景和目的-血管周围的脑肥大细胞（MC）已被证明参与实验性短暂性脑缺血后的急性血脑屏障破坏和扩张性脑水肿。然而，潜在的分子机制仍然未知。由于蛋白水解明胶酶、基质金属蛋白酶 (MMP)-2 和 MMP-9 被认为在缺血后损害血脑屏障的完整性方面具有核心作用，因此我们检查了脑 MC 是否影响缺血性脑微血管系统中的明胶酶活性。方法-大鼠经历 60 分钟的大脑中动脉闭塞，然后再灌注 3 小时，并接受 MC 稳定剂治疗（色甘酸盐），或 MC 脱颗粒（化合物 48/80）剂，或媒介物。经过基因改造的 MC 缺陷 WsRc(Ws/Ws) 大鼠及其野生型同窝大鼠 (WT) 经历了相同的程序。测量脑水肿和伊文思蓝白蛋白外渗。明胶酶活性通过原位酶谱法可视化，并通过计算机高通量图像和数据分析进行量化。结果-激活的 MC 显示出明胶酶阳性颗粒的分泌。遗传性 MC 缺乏降低了整体明胶酶活性面积（与 WT 相比，-69%；P < 0.001）和缺血微血管系统的平均明胶酶活性（与 WT 相比，-57%；P = 0.002）。用色甘酸盐稳定 MC 降低了具有高明胶酶活性的微血管的百分比（与盐水相比为-36%；P < 0.05）。化合物48/80显示缺血性损伤中原位酶谱活性面积增加（与盐水相比+55%；P = 0.001）。微血管明胶酶活性与脑肿胀相关（r = 0.84；P < 0.001；r = 0.61；P = 0.02）。结论 - 我们的数据表明，脑 MC 参与调节急性微血管明胶酶激活以及短暂性脑缺血后随之而来的血脑屏障破坏。 （中风。2011；42：3600-3605。）
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. (Stroke. 2011; 42: 3600-3605.)