title: Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage.
abstract: We tested the hypothesis that astrocytic matrix metalloproteinase-9 (MMP-9) mediates hemorrhagic brain edema. In a clinical case of hemorrhagic stroke, MMP-9 co-localized with astrocytes and neurons in peri-hematoma areas. In a mouse model where blood was injected into striatum, MMP-9 was colocalized with astrocytes surrounding the hemorrhagic lesion. Because MMP-9 is present in blood as well as brain, we compared four groups of wild type (WT) and MMP-9 knockout (KO) mice: WT blood injected into WT brain, KO blood into KO brain, WT blood into KO brain, and KO blood into WT brain. Gel zymography showed that MMP-9 was elevated in WT hemorrhagic brain tissue but absent from KO hemorrhagic brain tissue. Edematous water content was elevated when WT blood was injected into WT brain. However, edema was ameliorated when MMP-9 was absent in either blood or brain or both. To further assess the mechanisms involved in astrocytic induction of MMP-9, we next examined primary mouse astrocyte cultures. Exposure to hemoglobin rapidly upregulated MMP-9 in conditioned media within 1 to 24 h. Hemoglobin-induced MMP-9 was reduced by the free radical scavenger U83836E. Taken together, these data suggest that although there are large amounts of MMP-9 in blood, hemoglobin-induced oxidative stress can trigger MMP-9 in astrocytes and these parenchymal sources of matrix degradation may also be an important factor in the pathogenesis of hemorrhagic brain edema.
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
authors.forename: Emiri
authors.initials: E
authors.lastname: Tejima
authors.forename: Bing-Qiao
authors.initials: BQ
authors.lastname: Zhao
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tsuji
authors.forename: Anna
authors.initials: A
authors.lastname: Rosell
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
authors.forename: R Gilberto
authors.initials: RG
authors.lastname: Gonzalez
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D002543:Cerebral Hemorrhage / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology; D018384:Oxidative Stress / Q000502:physiology; D020521:Stroke / Q000150:complications / Q000378:metabolism / Q000473:pathology
chemical_list: D006454:Hemoglobins; D020780:Matrix Metalloproteinase 9