Early growth response-1 worsens ventilator-induced lung injury by up-regulating prostanoid synthesis.
Am J Respir Crit Care Med
; 181(9): 947-56, 2010 May 01.
Article
en En
| MEDLINE
| ID: mdl-20110555
RATIONALE: Ventilator-induced lung injury (VILI) is common and serious and may be mediated in part by prostanoids. We have demonstrated increased expression of the early growth response-1 (Egr1) gene by injurious ventilation, but whether-or how-such up-regulation contributes to injury is unknown. OBJECTIVES: We sought to define the role of Egr1 in the pathogenesis of VILI. METHODS: An in vivo murine model of VILI was used, and Egr1(+/+) (wild-type) and Egr1(-/-) mice were studied; the effects of prostaglandin E receptor subtype 1 (EP1) inhibition were assessed. MEASUREMENTS AND MAIN RESULTS: Injurious ventilation caused lung injury in wild-type mice, but less so in Egr1(-/-) mice. The injury was associated with expression of EGR1 protein, which was localized to type II cells and macrophages and was concentrated in nuclear extracts. There was a concomitant increase in expression of phosphorylated p44/p42 mitogen-activated protein kinases. The prostaglandin E synthase (mPGES-1) gene has multiple EGR1 binding sites on its promoter, and induction of mPGES-1 mRNA (as well as the prostanoid product, PGE2) by injurious ventilation was highly dependent on the presence of the Egr1 gene. PGE2 mediates many lung effects via EP1 receptors, and EP1 blockade (with ONO-8713) lessened lung injury. CONCLUSIONS: This is the first demonstration of a mechanism whereby expression of a novel gene (Egr1) can contribute to VILI via a prostanoid-mediated pathway.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Prostaglandinas
/
Proteína 1 de la Respuesta de Crecimiento Precoz
/
Lesión Pulmonar Inducida por Ventilación Mecánica
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Am J Respir Crit Care Med
Asunto de la revista:
TERAPIA INTENSIVA
Año:
2010
Tipo del documento:
Article
Pais de publicación:
Estados Unidos