RATIONALE:: 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