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Up-Regulation of Secretory Leukocyte Protease Inhibitor (SLPI) in the Brain after Ischemic Stroke: Adenoviral Expression of SLPI Protects Brain from Ischemic Injury

Department of Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pennsylvania (X.W., X.L., A.Y.-O., J.A.E., F.C.B., G.Z.F); and Department of Thrombosis Research, Bristol-Myers Squibb Company, Princeton, New Jersey (X.W., L.X., Y.Z.)

Secretory leukocyte protease inhibitor (SLPI) is a 12-kDa secreted protein initially identified from epithelial cells as an inhibitor of leukocyte serine proteases. In the present study, we described the identification of SLPI expression in ischemic cortex by suppression subtractive hybridization strategy. Our full-length rat SLPI cDNA shares 81% and 63% amino acid sequence identity with its mouse and human homologs, respectively, and with several polymorphisms to previous reported rat sequences. Northern blot analysis confirmed that SLPI mRNA was significantly induced in the ischemic brain tissue at 12 h (5.1-fold increase over sham controls, n = 4, p < 0.05), peaked at 2 days (26.1-fold increase, p < 0.001), and sustained up to 5 days (5.1-fold increase, p < 0.05). SLPI was localized in neurons and astrocytes in the peri-infarct zone from 24 to 72 h after middle cerebral artery occlusion by means of immunohistochemical and confocal microscopy analysis. Administration of a recombinant adenovirus overexpressing SLPI (Adv/SLPI) into the cortical tissue resulted in up to 58.4% reduction in ischemic lesion over controls at the site of Adv/SLPI expression (p < 0.01, n = 8) and significantly improved functional outcome (p < 0.01). These data suggest that the ischemia-induced expression of SLPI might play a neuroprotective role in focal stroke, possibly because of rapid inhibition of activated proteases and its suppression in inflammatory response.

Address correspondence to: Dr. Xinkang Wang, Department of Thrombosis Research, Bristol Myers Squibb Company, 311 Pennington Rocky Hill Road, Pennington, NJ 08534. E-mail: xinkang.wang{at}bms.com

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