Effective Treatment of Mouse Sepsis With an Inhibitory Antibody Targeting Integrin αvβ5

Objective: Integrin alpha v beta 5 has been identified as a regulator of vascular leak and endothelial permeability. We hypothesized that targeting alpha v beta 5 could represent a viable treatment strategy for sepsis. Design: Integrin beta 5 subunit knockout and wild-type 129/svJae mice and wild-type mice treated with alpha v beta 5 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 alpha v beta 5 antibodies to assess for effects on lipopolysaccharide-induced changes in transendothelial resistance and on patterns of cytoskeletal reorganization. Setting: Laboratory-based research. Subjects: Mice and endothelial cell monolayers. Interventions, Measurements, and Main Results: 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. beta 5 knockout mice had decreased mortality after intraperitoneal lipo-polysaccharide and cecal ligation and puncture and decreased vascular leak, as measured by extravasation of an I-125-labeled intravascular tracer. Treating clinically ill mice with alpha v beta 5 antibodies, up to 20 hrs after intraperitoneal lipopolysaccharide and cecal ligation and puncture, also resulted in decreased mortality. alpha v beta 5 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. alpha v beta 5 antibodies had no effect on cytokine/chemokine serum levels after cecal ligation and puncture. beta 5 knockout mice and wild-type controls did not exhibit differences in thioglyccolate-induced leukocyte migration. Conclusions: Our studies suggest that alpha v beta 5 is an important regulator of the vascular endothelial leak response in sepsis and that alpha v beta 5 blockade may provide a novel approach to treating this devastating disease syndrome. (Crit Care Med 2013; 41: 546-553)