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Molecular & Cellular Proteomics 2:234-241, 2003.
© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Blood-Brain Barrier Damage Induces Release of ₂-Macroglobulin^*

Luca Cucullo, Nicola Marchi, Matteo Marroni, Vincent Fazio, Shobu Namura and Damir Janigro^,,¶

Department of Neurological Surgery, Cerebrovascular Research Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195
Department of Cell Biology, Cerebrovascular Research Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195

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 ₂-macroglobulin (₂M). We hypothesized that BBB failure may result in increased ₂M 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 ₂M at 4 h after BBB disruption by hyperosmotic mannitol. In parallel in vitro experiments, we observed a similar increase of ₂M 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 ₂M by perivascular astrocytes as well as peripheral source.

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