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This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/H558    most recent 01275.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (67) Citing Articles via Google Scholar Google Scholar Articles by Gidday, J. M. Articles by Park, T. S. Search for Related Content PubMed PubMed Citation Articles by Gidday, J. M. Articles by Park, T. S.

Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia

Departments of ¹Neurosurgery, ²Cell Biology and Physiology, and ³Anatomy and Neurobiology, Washington University School of Medicine, and ⁴St. Louis Children's Hospital, St. Louis, Missouri; ⁵Departments of Anesthesiology, Pharmacology, Surgical Critical Care and Internal Medicine, and Neuroscience, Geneva University, Geneva, Switzerland; ⁶Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and ⁷Department of Neurosurgery and Department of Neurology and Neurological Sciences and Program in Neuroscience, Stanford University School of Medicine, Stanford, California

Submitted 16 December 2004 ; accepted in final form 4 March 2005

Results of recent studies reveal vascular and neuroprotective effects of matrix metalloproteinase-9 (MMP-9) inhibition and MMP-9 gene deletion in experimental stroke. However, the cellular source of MMP-9 produced in the ischemic brain and the mechanistic basis of MMP-9-mediated brain injury require elucidation. In the present study, we used MMP-9^–/– mice and chimeric knockouts lacking either MMP-9 in leukocytes or in resident brain cells to test the hypothesis that MMP-9 released from leukocytes recruited to the brain during postischemic reperfusion contributes to this injury phenotype. We also tested the hypothesis that MMP-9 promotes leukocyte recruitment to the ischemic brain and thus is proinflammatory. The extent of blood-brain barrier (BBB) breakdown, the neurological deficit, and the volume of infarction resulting from transient focal stroke were abrogated to a similar extent in MMP-9^–/– mice and in chimeras lacking leukocytic MMP-9 but not in chimeras with MMP-9-containing leukocytes. Zymography and Western blot analysis from these chimeras confirmed that the elevated MMP-9 expression in the brain at 24 h of reperfusion is derived largely from leukocytes. MMP-9^–/– mice exhibited a reduction in leukocyte-endothelial adherence and a reduction in the number of neutrophils plugging capillaries and infiltrating the ischemic brain during reperfusion; microvessel immunopositivity for collagen IV was also preserved in these animals. These latter results document proinflammatory actions of MMP-9 in the ischemic brain. Overall, our findings implicate leukocytes, most likely neutrophils, as a key cellular source of MMP-9, which, in turn, promotes leukocyte recruitment, causes BBB breakdown secondary to microvascular basal lamina proteolysis, and ultimately contributes to neuronal injury after transient focal stroke.

inflammation; stroke; endothelial cells; vascular permeability; mice

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