From the Institute of Clinical Chemistry, Department of Neurology, Department of Neuropathology, and Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Circ Res. 2013 Sep 27;113(8):1013-22. doi: 10.1161/CIRCRESAHA.113.301207. Epub 2013 Jun 18.
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.
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.
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 CEACAM1(+)matrix metalloproteinase-9(+) neutrophils in the ischemic hemispheres.
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.
血脑屏障（BBB）的破坏和脑水肿是由缺血后炎症引起的，导致缺血性脑卒中后的死亡率和发病率升高。癌胚抗原相关细胞粘附分子 1（CEACAM1）在再灌注损伤中的功能作用尚未得到证实。
我们试图确定并描述 CEACAM1 表达的炎症细胞在 Ceacam1（-/-）和野生型小鼠缺血性脑卒中后 BBB 破坏和结局中的相关性。
采用微丝法暂时性阻断大脑中动脉诱导局灶性缺血。通过 MRI 和 Evans 蓝通透性测定，我们观察到 Ceacam1（-/-）小鼠的中风体积增大、BBB 破坏和水肿形成、脑灌注减少以及脑萎缩。这导致了神经学评分下降和高卒中相关死亡率。通过免疫荧光、流式细胞术、酶谱分析和中性粒细胞刺激，证实了 Ceacam1（-/-）小鼠中性粒细胞浸润增加、中性粒细胞相关基质金属蛋白酶-9 的过度产生和释放。重要的是，在 Ceacam1（-/-）小鼠中中和基质金属蛋白酶-9 的活性足以减轻中风体积并将存活率提高到 CEACAM1 功能正常的动物水平。对小鼠和人类中风后尸检大脑的免疫组织化学分析一致表明，缺血半球中 CEACAM1（+）基质金属蛋白酶-9（+）中性粒细胞丰富。
CEACAM1 控制缺血后炎症时 BBB 处中性粒细胞的基质金属蛋白酶-9 分泌。我们提出 CEACAM1 是局灶性脑缺血中中性粒细胞介导的组织损伤和 BBB 破坏的重要抑制调节因子。
