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Integrin αvβ5 has been identified as a regulator of vascular leak and endothelial permeability. We hypothesized that targeting αvβ5 could represent a viable treatment strategy for sepsis.Integrin β5 subunit knockout and wild-type 129/svJae mice and wild-type mice treated with αvβ5 blocking or control antibodies were tested in models of intraperitoneal lipopolysaccharide and cecal ligation and puncture. Human umbilical vein endothelial cell and human lung microvascular endothelial cell monolayers were treated with αvβ5 antibodies to assess for effects on lipopolysaccharide-induced changes in transendothelial resistance and on patterns of cytoskeletal reorganization.Laboratory-based research.Mice and endothelial cell monolayers.Measurements taken after intraperitoneal lipopolysaccharide and/or cecal ligation and puncture included mortality, vascular leak, hematocrit, quantification of a panel of serum cytokines/chemokines, and assessment of thioglyccolate-induced leukocyte migration. β5 knockout mice had decreased mortality after intraperitoneal lipopolysaccharide and cecal ligation and puncture and decreased vascular leak, as measured by extravasation of an I125-labeled intravascular tracer. Treating clinically ill mice with αvβ5 antibodies, up to 20 hrs after intraperitoneal lipopolysaccharide and cecal ligation and puncture, also resulted in decreased mortality. αvβ5 antibodies attenuated lipopolysaccharide-induced transendothelial resistance changes and cytoskeletal stress fiber formation in both human umbilical vein endothelial cell and human lung microvascular endothelial cell monolayers. αvβ5 antibodies had no effect on cytokine/chemokine serum levels after cecal ligation and puncture. β5 knockout mice and wild-type controls did not exhibit differences in thioglyccolate-induced leukocyte migration.Our studies suggest that αvβ5 is an important regulator of the vascular endothelial leak response in sepsis and that αvβ5 blockade may provide a novel approach to treating this devastating disease syndrome.