Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen species-dependent pathways

Background: astrocytes are an integral component of the blood-brain barrier (bbb) which may be compromised by ischemic or traumatic brain injury. in response to trauma,astrocytes increase expression of the endopeptidase matrix metalloproteinase (mmp)-9. compromise of the bbb leads to the infiltration of fluid and blood-derived proteins including albumin into the brain parenchyma. albumin has been previously shown to activate astrocytes and induce the production of inflammatory mediators. the effect of albumin on mmp-9 activation in astrocytes is not known. we investigated the molecular mechanisms underlying the production of mmp-9 by albumin in astrocytes.methods: primary enriched astrocyte cultures were used to investigate the effects of exposure to albumin on the release of mmp-9. mmp-9 expression was analyzed by zymography. the involvement of mitogen-activated protein kinase (mapk),reactive oxygen species (ros) and the tgf-β receptor-dependent pathways were investigated using pharmacological inhibitors. the production of ros was observed by dichlorodihydrofluorescein diacetate fluorescence. the level of the mmp-9 inhibitor tissue inhibitor of metalloproteinase (timp)-1 produced by astrocytes was measured by elisa.results: we found that albumin induces a time-dependent release of mmp-9 via the activation of p38 mapk and extracellular signal regulated kinase,but not jun kinase. albumin-induced mmp-9 production also involves ros production upstream of the mapk pathways. however,albumin-induced increase in mmp-9 is independent of the tgf-β receptor,previously described as a receptor for albumin. albumin also induces an increase in timp-1 via an undetermined mechanism.conclusions: these results link albumin (acting through ros and the p38 mapk) to the activation of mmp-9 in astrocytes. numerous studies identify a role for mmp-9 in the mechanisms of compromise of the bbb,epileptogenesis,or synaptic remodeling after ischemia or traumatic brain injury. the increase in mmp-9 produced by albumin further implicates both astrocytes and albumin in the acute and long-term complications of acute cns insults,including cerebral edema and epilepsy. © 2012 ralay ranaivo et al.; licensee biomed central ltd.