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Am J Physiol Heart Circ Physiol (March 11, 2005). doi:10.1152/ajpheart.01275.2004
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Submitted on December 17, 2004
Accepted on March 4, 2005

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

Jeffrey M Gidday1*, Yvan G Gasche1, Jean-Christophe Copin1, Aarti R Shah1, Ronaldo S Perez1, Steven D Shapiro1, Pak H Chan1, and Tae S Park1

1 Neurosurgery, Cell Biology & Physiology, Washington University, St. Louis, MO, USA

* To whom correspondence should be addressed. E-mail: gidday{at}nsurg.wustl.edu.

Results of recent studies reveal vascular and neuroprotective effects of matrix metalloproteinase-9 (MMP9) inhibition and MMP9 gene deletion in experimental stroke. However, the cellular source of MMP9 produced in ischemic brain and the mechanistic basis of MMP9-mediated brain injury require elucidation. In the present study, we used MMP9-/- mice and chimeric knockouts lacking either MMP9 in leukocytes or in resident brain cells to test the hypothesis that MMP9 released from leukocytes recruited to the brain during postischemic reperfusion contributes to this injury phenotype. We also tested the hypothesis that MMP9 promotes leukocyte recruitment to ischemic brain and thus is pro-inflammatory. The extent of BBB breakdown, the neurologic deficit, and the volume of infarction resulting from transient focal stroke were abrogated to a similar extent in MMP9-/- mice and in chimeras lacking leukocytic MMP9, but not in chimeras with MMP9-containing leukocytes. Zymography and western blots from these chimeras confirmed that the elevated MMP9 expression in brain at 24 h of reperfusion is derived largely from leukocytes. MMP9-/- mice exhibited a reduction in leukocyte-endothelial adherence, and a reduction in the number of neutrophils plugging capillaries and infiltrating ischemic brain during reperfusion; microvessel immunopositivity for collagen IV was also preserved in these animals. These latter results document proinflammatory actions of MMP9 in ischemic brain. Overall, our findings implicate leukocytes, most likely neutrophils, as a key cellular source of MMP9 that in turn promotes leukocyte recruitment, causes BBB breakdown secondary to microvascular basal lamina proteolysis, and ultimately contributes to neuronal injury following transient focal stroke.




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