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首页> 外文期刊>Circulation research: a journal of the American Heart Association >Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke
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Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke

机译：癌胚抗原相关细胞粘附分子1在缺血性中风小鼠模型中抑制MMP-9介导的血脑屏障破坏

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RATIONALE: Blood-brain-barrier (BBB) breakdown and cerebral edema result from postischemic inflammation and contribute to mortality and morbidity after ischemic stroke. A functional role for the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the regulation of reperfusion injury has not yet been demonstrated. OBJECTIVE: We sought to identify and characterize the relevance of CEACAM1-expressing inflammatory cells in BBB breakdown and outcome after ischemic stroke in Ceacam1 and wild-type mice. METHODS AND RESULTS: Focal ischemia was induced by temporary occlusion of the middle cerebral artery with a microfilament. Using MRI and Evans blue permeability assays, we observed increased stroke volumes, BBB breakdown and edema formation, reduction of cerebral perfusion, and brain atrophy in Ceacam1 mice. This translated into poor performance in neurological scoring and high poststroke-associated mortality. Elevated neutrophil influx, hyperproduction, and release of neutrophil-related matrix metalloproteinase-9 in Ceacam1 mice were confirmed by immune fluorescence, flow cytometry, zymography, and stimulation of neutrophils. Importantly, neutralization of matrix metalloproteinase-9 activity in Ceacam1 mice was sufficient to alleviate stroke sizes and improve survival to the level of CEACAM1-competent animals. Immune histochemistry of murine and human poststroke autoptic brains congruently identified abundance of CEACAM1matrix metalloproteinase-9 neutrophils in the ischemic hemispheres. CONCLUSIONS: CEACAM1 controls matrix metalloproteinase-9 secretion by neutrophils in postischemic inflammation at the BBB after stroke. We propose CEACAM1 as an important inhibitory regulator of neutrophil-mediated tissue damage and BBB breakdown in focal cerebral ischemia.
机译：理由：缺血后炎症导致血脑屏障（BBB）分解和脑水肿，并导致缺血性中风后的死亡率和发病率。尚未证明癌胚抗原相关细胞粘附分子1（CEACAM1）在调节再灌注损伤中的功能。目的：我们试图鉴定和表征表达CEACAM1的炎性细胞与Ceacam1和野生型小鼠缺血性中风后BBB分解和转归的相关性。方法与结果：局灶性缺血是由于大脑中动脉暂时被微丝阻塞所致。使用MRI和Evans blue通透性测定，我们观察到Ceacam1小鼠的中风量增加，BBB分解和水肿形成，脑灌注减少以及脑萎缩。这导致神经系统评分差和中风后相关死亡率高。通过免疫荧光，流式细胞仪，酶谱法和刺激嗜中性粒细胞，证实Ceacam1小鼠中嗜中性粒细胞大量流入，过度生产和释放，与嗜中性粒细胞相关的基质金属蛋白酶9相关。重要的是，中和Ceacam1小鼠中基质金属蛋白酶9的活性足以减轻中风的大小并提高生存能力，达到CEACAM1能力的动物水平。小鼠和人类中风后的自闭症大脑的免疫组织化学一致地确定了缺血半球中CEACAM1基质金属蛋白酶9中性粒细胞的丰度。结论：CEACAM1控制中性粒细胞在中风后血脑屏障缺血后炎症中由中性粒细胞分泌基质金属蛋白酶9。我们建议CEACAM1作为中性粒细胞介导的组织损伤和局灶性脑缺血中BBB分解的重要抑制性调节剂。

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