Leukocyte_derived matrix metalloproteinase_9 mediates blood_brain barrier breakdown and is.pdf

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Leukocyte_derived matrix metalloproteinase_9 mediates blood_brain barrier breakdown and is.pdf

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Leukocyte_derived matrix metalloproteinase_9 mediates blood_brain barrier breakdown and is

Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia Jeffrey M. Gidday,1,2,4 Yvan G. Gasche,5,7 Jean-C. Copin,5,7 Aarti R. Shah,1 Ronald S. Perez,1 Steven D. Shapiro,6 Pak H. Chan,7 and T. S. Park1,3,4 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 Gidday, Jeffrey M., Yvan G. Gasche, Jean-C. Copin, Aarti R. Shah, Ronald S. Perez, Steven D. Shapiro, Pak H. Chan, and T. S. Park. Leukocyte-derived matrix metalloproteinase-9 medi- ates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289: H558 –H568, 2005. First published March 11, 2005; doi:10.1152/ajpheart.01275.2004.—Results of recent studies re- veal vascular and neuroprotective effects of matrix metalloprotein- ase-9 (MMP-9) inhibition and MMP-9 gene deletion in experimen- tal 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