Justicia Carles, Martín Abraham, Rojas Santiago, Gironella Meritxell, Cervera Alvaro, Panés Julián, Chamorro Angel, Planas Anna M
Department of Pharmacology and Toxicology, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
J Cereb Blood Flow Metab. 2006 Mar;26(3):421-32. doi: 10.1038/sj.jcbfm.9600198.
Cerebral ischemia triggers an inflammatory process involving the infiltration of leukocytes to the parenchyma. Circulating leukocytes adhere to the vascular wall through adhesion molecules. Here we quantified the in vivo expression of vascular cell adhesion molecule-1 (VCAM-1) in the brain, heart and lungs from 6 to 48 h after transient middle cerebral artery (MCA) occlusion in rats, by intravenous injection of a tracer radiolabelled anti-VCAM-1 antibody. The vascular localization of VCAM-1 was verified by immunohistochemistry after in vivo injection of the antibody. Vascular cell adhesion molecule-1 was strongly induced (4-fold at 24 h) in the microvasculature of the ischemic area, and, to a lesser extent, in the contralateral hemisphere and in a remote organ, the heart, but not in the lungs, indicating that the inflammatory process propagates beyond the injured brain. We injected intravenously either blocking doses of anti-VCAM-1 antibodies or control antibodies after MCA occlusion in rats and mice. We evaluated the neurological score in rats, and infarct volume at 2 days in rats and at 4 days in mice. Anti-VCAM-1 did not protect against ischemic damage either in rats or in mice. Vascular cell adhesion molecule-1 blockade significantly decreased the number of ED1 (labeling monocytes /macrophages/reactive microglia)-positive cells in the ischemic rat brain. However, it did not reduce the numbers of infiltrating neutrophils and lymphocytes, and total leukocytes (CD45 positive), which showed a trend to increase. The results show vascular upregulation of VCAM-1 after transient focal ischemia, but no benefits of blocking VCAM-1, suggesting that this is not a therapeutical strategy for stroke treatment.
脑缺血引发炎症反应，包括白细胞浸润至脑实质。循环中的白细胞通过黏附分子黏附于血管壁。在此，我们通过静脉注射放射性标记的抗血管细胞黏附分子-1（VCAM-1）抗体示踪剂，对大鼠大脑中动脉短暂闭塞后6至48小时内大脑、心脏和肺中VCAM-1的体内表达进行了定量。体内注射抗体后，通过免疫组织化学验证了VCAM-1的血管定位。VCAM-1在缺血区域的微血管中被强烈诱导（24小时时增加4倍），在对侧半球以及远处器官心脏中也有较小程度的诱导，但在肺中未被诱导，这表明炎症反应超出了受损大脑的范围。在大鼠和小鼠大脑中动脉闭塞后，我们静脉注射了阻断剂量的抗VCAM-1抗体或对照抗体。我们评估了大鼠的神经功能评分，以及大鼠2天时和小鼠4天时的梗死体积。抗VCAM-1抗体在大鼠和小鼠中均未对缺血损伤起到保护作用。VCAM-1阻断显著减少了缺血大鼠脑中ED1（标记单核细胞/巨噬细胞/反应性小胶质细胞）阳性细胞的数量。然而，它并未减少浸润的中性粒细胞和淋巴细胞数量以及总白细胞（CD45阳性）数量，后者呈增加趋势。结果表明短暂局灶性缺血后血管中VCAM-1上调，但阻断VCAM-1并无益处，提示这不是一种治疗中风的策略。
