Increased Akt-mTOR Signaling in Lung Epithelium Is Associated with Respiratory Distress Syndrome in Mice
Increased Akt-mTOR Signaling in Lung Epithelium Is Associated with Respiratory Distress Syndrome in Mice
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DOI：
10.1128/mcb.00732-10
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发表时间：
2011-03-01
影响因子：
5.3
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Ikeda, Hiroyuki;Shiojima, Ichiro;Komuro, Issei
糖尿病妇女怀孕与围产期并发症的风险较高有关。特别是，糖尿病母亲的婴儿经常患有呼吸窘迫综合征（RDS），这是早产儿死亡的主要原因，并且被认为主要是由于婴儿中响应于母亲高血糖症的高胰岛素血症。为了阐明胰岛素信号如何诱导RDS，支气管肺泡上皮特异性Akt 1转基因（TG）小鼠的机制。Akt 1在胎肺上皮中的过度表达导致在胚胎第18.5天（E18.5）通过剖腹产出生的早产儿的RDS。低氧诱导因子2 α（HIF-2 α）及其靶血管内皮生长因子（VEGF）在Akt 1 TG小鼠肺中的表达水平下调。通过雷帕霉素抑制Akt-哺乳动物雷帕霉素靶蛋白（mTOR）信号传导轴恢复了VEGF的表达，并改善了Akt 1 TG幼仔的肺病理学。雷帕霉素还减弱了在E17.5早产的野生型小鼠中的RDS表型。在培养的肺上皮细胞中，胰岛素以mTOR依赖的方式降低VEGF表达和VEGF启动子上HIF-2的转录活性。因此，肺上皮细胞中Akt-mTOR通路的异常激活在婴儿RDS的发病机制中起着因果作用，可能是通过下调肺中HIF-2依赖的VEGF表达。
Pregnancy in women with diabetes is associated with a higher risk of perinatal complications. In particular, infants of diabetic mothers frequently suffer from respiratory distress syndrome (RDS), which is a leading cause of death in preterm infants and is considered to be primarily due to hyperinsulinemia in infants in response to maternal hyperglycemia. To elucidate the mechanism of how insulin signaling induces RDS, bronchoalveolar epithelium-specific Akt1 transgenic (TG) mice were generated. Akt1 overexpression in fetal lung epithelium resulted in RDS in preterm infants born by Caesarean section at embryonic day 18.5 (E18.5). The expression levels of hypoxia-inducible factor 2 alpha (HIF-2 alpha) and its target vascular endothelial growth factor (VEGF) were downregulated in the lung of Akt1 TG mice. Inhibition of the Akt-mammalian target of rapamycin (mTOR) signaling axis by rapamycin restored the expression of VEGF and improved the lung pathology of Akt1 TG pups. Rapamycin also attenuated the RDS phenotype in wild-type mice delivered preterm at E17.5. In cultured lung epithelial cells, insulin reduced VEGF expression and transcriptional activity of HIF-2 on VEGF promoter in an mTOR-dependent manner. Thus, aberrant activation of the Akt-mTOR pathway in lung epithelium plays a causal role in the pathogenesis of infant RDS, presumably through downregulation of HIF-2-dependent VEGF expression in the lung.