Blood-brain barrier (BBB) failure occurs in many neurological diseases and is caused in part by activation of pro-inflammatory factors including matrix metalloproteinases (MMPs). Counterbalancing, ¡§BBB protective¡¨ cascades have recently been described, including NO-mediated Interleukin-6 (IL-6) release by glia. IL-6 has been shown to trigger production of MMPs 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 (BBBD) for intrarterial chemotherapy of brain tumors. Serum samples revealed significantly increased levels of 2M at 4 hours after BBBD. 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 bi-dimensional gel electrophoresis, and mass-spectrometry followed by Western blotting immunodetection. We conclude that in addition to pro-inflammatory changes, BBB failure may also trigger protective release of 2M by perivascular astrocytes as well as peripheral source.