title: Effective treatment of mouse sepsis with an inhibitory antibody targeting integrin αvβ5.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Laboratory-based research.
  
  
  METHODS
  Mice and endothelial cell monolayers.
  
  
  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. β5 knockout mice had decreased mortality after intraperitoneal lipopolysaccharide and cecal ligation and puncture and decreased vascular leak, as measured by extravasation of an I-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Lung Biology Center, University of California, San Francisco, CA, USA. george.su@ucsf.edu
authors.forename: George
authors.initials: G
authors.lastname: Su
authors.forename: Amha
authors.initials: A
authors.lastname: Atakilit
authors.forename: John T
authors.initials: JT
authors.lastname: Li
authors.forename: Nanyan
authors.initials: N
authors.lastname: Wu
authors.forename: Jacky
authors.initials: J
authors.lastname: Luong
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.forename: Mallar
authors.initials: M
authors.lastname: Bhattacharya
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002432:Cecum / Q000601:surgery; D002465:Cell Movement; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D007962:Leukocytes / Q000502:physiology; D008026:Ligation; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D011677:Punctures; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000235:genetics; D018805:Sepsis / Q000628:therapy*
chemical_list: D000906:Antibodies; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5