Mast cells promote blood brain barrier breakdown and neutrophil infiltration in a mouse model of focal cerebral ischemia
Mast cells promote blood brain barrier breakdown and neutrophil infiltration in a mouse model of focal cerebral ischemia
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DOI：
10.1038/jcbfm.2014.239
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发表时间：
2015-04-01
影响因子：
6.3
通讯作者：
Carswell, Hilary V. O.
中科院分区：
文献类型：
--
作者：
McKittrick, Craig M.;Lawrence, Catherine E.;Carswell, Hilary V. O.
血脑屏障（BBB）破坏和神经炎症是缺血性卒中发病率和死亡率的关键事件。本研究探讨了肥大细胞缺乏和稳定对小鼠短暂性大脑中动脉闭塞（tMCAo）后血脑屏障破坏和中性粒细胞浸润的影响。成年雄性C57 BL 6/J野生型（WT）和肥大细胞缺陷型（C57 BL 6/J KitWsh/Wsh（Wsh））小鼠经历tMCAo和BBB破坏，在再灌注4小时后检查脑水肿和中性粒细胞浸润。与WT小鼠相比，Wsh小鼠的血脑屏障破坏、脑水肿和中性粒细胞浸润显著减少（P < 0.05）。这些结果重复使用肥大细胞稳定剂，色甘酸盐。与媒介物相比，心室内施用色甘酸盐的野生型小鼠表现出减少的BBB破坏、脑水肿和中性粒细胞浸润（P < 0.05）。在Wsh小鼠中，色甘酸盐与载体相比没有影响，验证了色甘酸盐对脑肥大细胞的特异性。蛋白质组学分析表明，Wsh与WT的影响可能是通过表达内皮糖蛋白，内皮素-1，基质金属蛋白酶-9。使用肥大细胞缺陷的体内模型，这是第一项研究表明肥大细胞促进小鼠局灶性缺血中的BBB破坏，并为使用小鼠识别肥大细胞相关的BBB损伤的特定机制开辟了未来的机会。
Blood brain barrier (BBB) breakdown and neuroinflammation are key events in ischemic stroke morbidity and mortality. The present study investigated the effects of mast cell deficiency and stabilization on BBB breakdown and neutrophil infiltration in mice after transient middle cerebral artery occlusion (tMCAo). Adult male C57BL6/J wild type (WT) and mast cell-deficient (C57BL6/J KitWsh/Wsh (Wsh)) mice underwent tMCAo and BBB breakdown, brain edema and neutrophil infiltration were examined after 4 hours of reperfusion. Blood brain barrier breakdown, brain edema, and neutrophil infiltration were significantly reduced in Wsh versus WT mice (P < 0.05). These results were reproduced pharmacologically using mast cell stabilizer, cromoglycate. Wild-type mice administered cromoglycate intraventricularly exhibited reduced BBB breakdown, brain edema, and neutrophil infiltration versus vehicle (P < 0.05). There was no effect of cromoglycate versus vehicle in Wsh mice, validating specificity of cromoglycate on brain mast cells. Proteomic analysis in Wsh versus WT indicated that effects may be via expression of endoglin, endothelin-1, and matrix metalloproteinase-9. Using an in vivo model of mast cell deficiency, this is the first study showing that mast cells promote BBB breakdown in focal ischemia in mice, and opens up future opportunities for using mice to identify specific mechanisms of mast cell-related BBB injury.