Blood-brain barrier damage induces release of α2-macroglobulin
Blood-brain barrier damage induces release of α2-macroglobulin
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DOI：
10.1074/mcp.m200077-mcp200
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发表时间：
2003-04-01
影响因子：
7
通讯作者：
Janigro, D
中科院分区：
文献类型：
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作者：
Cucullo, L;Marchi, N;Janigro, D
血脑屏障（BBB）衰竭发生在许多神经系统疾病中，部分是由包括基质金属蛋白酶在内的促炎因子的激活引起的。平衡，“血脑屏障保护”级联反应最近被描述，包括no介导的胶质细胞释放白细胞介素6。白细胞介素6已被证明可触发基质金属蛋白酶抑制剂如α(2)-巨球蛋白（α (2)M）的产生。我们假设血脑屏障衰竭可能导致血管周围星形胶质细胞释放α (2)M增加。这项研究最初是在接受高渗甘露醇动脉化疗的脑肿瘤患者中进行的医源性血脑屏障破坏试验。血清样本显示，高渗甘露醇破坏血脑屏障后4小时α (2)M水平显著升高。在平行的体外实验中，我们观察到星形胶质细胞在模拟血脑屏障衰竭和血管周围水肿的条件下释放α (2)M的类似增加。在这两个实验中，蛋白质分析最初是通过双向凝胶电泳和质谱分析进行的，然后是免疫印迹检测。我们得出结论，除了促炎变化，血脑屏障衰竭也可能触发血管周围星形胶质细胞和外周来源的α (2)M的保护性释放。
Blood-brain barrier (BBB) failure occurs in many neurological diseases and is caused in part by activation of proinflammatory factors including matrix metalloproteinases. Counterbalancing, "BBB protective" cascades have recently been described, including NO-mediated interleukin 6 release by glia. Interleukin 6 has been shown to trigger production of matrix metalloproteinase inhibitors such as alpha(2)-macroglobulin (alpha(2)M). We hypothesized that BBB failure may result in increased alpha(2)M release by perivascular astrocytes. This was initially tested in patients undergoing iatrogenic BBB disruption by hyperosmotic mannitol for intra-arterial chemotherapy of brain tumors. Serum samples revealed significantly increased levels of alpha(2)M at 4 h after BBB disruption by hyperosmotic mannitol. In parallel in vitro experiments, we observed a similar increase of alpha(2)M release by astrocytes under conditions mimicking BBB failure and perivascular edema. For both experiments, protein analysis was initially performed by bidimensional gel electrophoresis and mass spectrometry followed by Western blotting immunodetection. We conclude that, in addition to proinflammatory changes, BBB failure may also trigger protective release of alpha(2)M by perivascular astrocytes as well as peripheral source.