Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
J Cereb Blood Flow Metab. 2010 Dec;30(12):1939-50. doi: 10.1038/jcbfm.2010.45. Epub 2010 Mar 31.
Hemoglobin (Hb) released from extravasated erythrocytes is implicated in brain edema after intracerebral hemorrhage (ICH). Hemoglobin is a major component of blood and a potent mediator of oxidative stress after ICH. Oxidative stress and matrix metalloproteinases (MMPs) are associated with blood-brain barrier (BBB) dysfunction. This study was designed to elucidate whether Hb-induced oxidative stress contributes to MMP-9 activation and BBB dysfunction in vivo. An intracerebral injection of Hb into rat striata induced increased hydroethidine (HEt) signals in parallel with MMP-9 levels. In situ gelatinolytic activity colocalized with oxidized HEt signals in vessel walls, accompanied by immunoglobulin G leakage and a decrease in immunoactivity of endothelial barrier antigen, a marker of endothelial integrity. Administration of a nonselective MMP inhibitor prevented MMP-9 levels and albumin leakage in injured striata. Moreover, reduction in oxidative stress by copper/zinc-superoxide dismutase (SOD1) overexpression reduced oxidative stress, MMP-9 levels, albumin leakage, and subsequent apoptosis compared with wild-type littermates. We speculate that Hb-induced oxidative stress may contribute to early BBB dysfunction and subsequent apoptosis, partly through MMP activation, and that SOD1 overexpression may reduce Hb-induced oxidative stress, BBB dysfunction, and apoptotic cell death.
从脑出血（ICH）后外渗的红细胞中释放的血红蛋白（Hb）与脑水肿有关。血红蛋白是血液的主要成分，也是 ICH 后氧化应激的主要介质。氧化应激和基质金属蛋白酶（MMPs）与血脑屏障（BBB）功能障碍有关。本研究旨在阐明 Hb 诱导的氧化应激是否导致 MMP-9 激活和体内 BBB 功能障碍。将 Hb 注入大鼠纹状体可诱导羟乙基噻吩（HEt）信号与 MMP-9 水平平行增加。原位明胶酶活性与血管壁中氧化的 HEt 信号共定位，伴有免疫球蛋白 G 渗漏和内皮屏障抗原免疫活性降低，内皮完整性的标志物。非选择性 MMP 抑制剂的给药可防止损伤纹状体中的 MMP-9 水平和白蛋白渗漏。此外，与野生型同窝仔相比，铜/锌-超氧化物歧化酶（SOD1）过表达减少氧化应激，降低 MMP-9 水平、白蛋白渗漏和随后的细胞凋亡。我们推测，Hb 诱导的氧化应激可能导致早期 BBB 功能障碍和随后的细胞凋亡，部分通过 MMP 激活，而过表达 SOD1 可减少 Hb 诱导的氧化应激、BBB 功能障碍和凋亡性细胞死亡。
