C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent
C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent
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DOI：
10.1038/sj.jcbfm.9600608
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发表时间：
2008-05-01
影响因子：
6.3
通讯作者：
Connolly, E. Sander
中科院分区：
文献类型：
--
作者：
Ducruet, Andrew F.;Hassid, Benjamin G.;Connolly, E. Sander
补体过敏毒素C3 a参与了小鼠脑缺血后的损伤。本研究评估了C3 a受体拮抗剂（C3 aRA）对缺血区白细胞浸润的影响。在野生型C57 B1/6小鼠中诱导短暂或永久性大脑中动脉闭塞（MCAO）。在闭塞前45分钟或闭塞后1小时腹膜内施用C3 aRA或媒介物。闭塞后24小时，我们收获脑组织并使用流式细胞术纯化炎性细胞。可溶性细胞间粘附分子（ICAM）-1蛋白水平采用酶联免疫吸附试验进行了评估，ICAM-1和C3 a受体（C3 aR）的表达通过免疫组化证实。在短暂性MCAO模型中，接受C3 aRA的动物显示出较小的中风，C3 aR阳性粒细胞的上调较少，内皮细胞上的ICAM-1蛋白比溶剂处理的动物少;在其他炎性细胞群中未观察到显著差异。C3 a受体拮抗剂治疗和溶剂治疗的动物在永久性MCAO后的每搏输出量或炎性细胞群无差异。这些数据表明，阻断C3 a与C3 aR的结合通过抑制中性粒细胞向缺血区的募集来调节再灌注卒中中的组织损伤。它进一步确立了C3 a过敏毒素的拮抗作用作为改善缺血/再灌注后损伤的有前景的策略。
The complement anaphylatoxin C3a contributes to injury after cerebral ischemia in mice. This study assesses the effect of C3a receptor antagonist (C3aRA) on leukocyte infiltration into the ischemic zone. Transient or permanent middle cerebral artery occlusion (MCAO) was induced in wild-type C57BI/6 mice. Intraperitoneal C3aRA or vehicle was administered 45 mins before or 1 h after occlusion. Twenty-four hours after occlusion, we harvested brain tissue and purified inflammatory cells using flow cytometry. Soluble intercellular adhesion molecule (ICAM)-1 protein levels were assessed using enzyme-linked immunosorbent assays, and ICAM-1 and C3a receptor (C3aR) expression was confirmed via immunohistochemistry. In the transient MCAO model, animals receiving C3aRA showed smaller strokes, less upregulation of C3aR-positive granulocytes, and less ICAM-1 protein on endothelial cells than vehicle-treated animals; no significant differences in other inflammatory cell populations were observed. C3a receptor antagonist-treated and vehicle-treated animals showed no differences in stroke volume or inflammatory cell populations after permanent MCAO. These data suggest that blocking the binding of C3a to C3aR modulates tissue injury in reperfused stroke by inhibiting the recruitment of neutrophils to the ischemic zone. It further establishes antagonism of the C3a anaphylatoxin as a promising strategy for ameliorating injury after ischemia/reperfusion.