Early growth response-1 worsens ventilator-induced lung injury by up-regulating prostanoid synthesis.
BACKGROUND
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.


OBJECTIVE
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.


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.
Ngiam
Nicola
N
Physiology and Experimental Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Peltekova
Vanya
V
Engelberts
Doreen
D
Otulakowski
Gail
G
Post
Martin
M
Kavanagh
Brian P
BP
D000818:Animals; D001665:Binding Sites; D051766:Early Growth Response Protein 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D011453:Prostaglandins / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D055397:Ventilator-Induced Lung Injury / Q000209:etiology* / Q000378:metabolism
D051766:Early Growth Response Protein 1; D011453:Prostaglandins