Physiology and Experimental Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Am J Respir Crit Care Med. 2010 May 1;181(9):947-56. doi: 10.1164/rccm.200908-1297OC. Epub 2010 Jan 28.
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.
We sought to define the role of Egr1 in the pathogenesis of VILI.
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.
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.
This is the first demonstration of a mechanism whereby expression of a novel gene (Egr1) can contribute to VILI via a prostanoid-mediated pathway.
呼吸机相关性肺损伤（VILI）较为常见且较为严重，其部分发病机制可能与前列腺素有关。我们已经证明损伤性通气会导致早期生长反应因子 1（Egr1）基因的表达增加，但这种上调是否以及如何导致损伤尚不清楚。
我们旨在确定 Egr1 在 VILI 发病机制中的作用。
使用体内小鼠 VILI 模型，研究 Egr1(+/+)（野生型）和 Egr1(-/-) 小鼠；评估前列腺素 E 受体亚型 1（EP1）抑制的作用。
损伤性通气会导致野生型小鼠的肺损伤，但在 Egr1(-/-) 小鼠中则较轻。损伤与 EGR1 蛋白的表达有关，该蛋白定位于 II 型细胞和巨噬细胞，且集中在核提取物中。同时，磷酸化 p44/p42 丝裂原活化蛋白激酶的表达也增加。前列腺素 E 合酶（mPGES-1）基因的启动子上有多个 EGR1 结合位点，损伤性通气诱导 mPGES-1 mRNA（以及前列腺素产物 PGE2）的表达高度依赖于 Egr1 基因的存在。PGE2 通过 EP1 受体介导许多肺效应，而 EP1 阻断（用 ONO-8713）可减轻肺损伤。
这是首次证明一种新基因（Egr1）的表达可以通过前列腺素介导的途径导致 VILI 的机制。
