Effective treatment of mouse sepsis with an inhibitory antibody targeting integrin αvß5.
Crit Care Med
; 41(2): 546-53, 2013 Feb.
Article
en En
| MEDLINE
| ID: mdl-23263571
ABSTRACT
OBJECTIVE:
Integrin αvß5 has been identified as a regulator of vascular leak and endothelial permeability. We hypothesized that targeting αvß5 could represent a viable treatment strategy for sepsis.DESIGN:
Integrin ß5 subunit knockout and wild-type 129/svJae mice and wild-type mice treated with αvß5 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 αvß5 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 MAINRESULTS:
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. ß5 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 αvß5 antibodies, up to 20 hrs after intraperitoneal lipopolysaccharide and cecal ligation and puncture, also resulted in decreased mortality. αvß5 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. αvß5 antibodies had no effect on cytokine/chemokine serum levels after cecal ligation and puncture. ß5 knockout mice and wild-type controls did not exhibit differences in thioglyccolate-induced leukocyte migration.CONCLUSIONS:
Our studies suggest that αvß5 is an important regulator of the vascular endothelial leak response in sepsis and that αvß5 blockade may provide a novel approach to treating this devastating disease syndrome.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
4_TD
/
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
4_sepsis
/
6_other_blood_disorders
Asunto principal:
Sepsis
/
Receptores de Vitronectina
/
Anticuerpos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Crit Care Med
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos