Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia
Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia
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DOI：
10.1152/ajplung.90487.2008
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发表时间：
2009-04-01
影响因子：
4.9
通讯作者：
Biswal, Shyam
中科院分区：
文献类型：
--
作者：
McGrath-Morrow, Sharon;Lauer, Thomas;Biswal, Shyam
[10] McGrath-Morrow S，劳尔T，Yee M，Neptune E，Podowski M，Thimmulappa RK，O'Reilly M，Biswal S. nrf 2增加新生小鼠暴露于高氧的存活率并减弱肺泡生长抑制。美国生理学杂志肺细胞分子生理学296：L565-L573，2009年。首次发表于2009年1月16日; doi：10.1152/ajplung.90487.2008。氧化应激增加与围产期窒息和新生儿期呼吸窘迫有关。核因子红细胞2 p45相关因子（Nrf 2）的诱导已被证明可以通过调节特定的基因途径降低氧化应激。我们假设，Nrf 2减弱新生小鼠暴露于高氧的死亡率和肺泡生长抑制。Nrf 2（+/+）和Nrf 2（-/-）新生小鼠在24 h暴露于高氧。暴露于高氧72 h并返回室内空气的Nrf 2（-/-）小鼠的存活率显著降低（P < 0.0001），而暴露于高氧连续8天的Nrf 2（-/-）小鼠的存活率显著降低（P < 0.005）。为了确定Nrf 2靶基因对高氧的反应，使用实时PCR从新生小鼠的肺测量谷胱甘肽过氧化物酶2（Gpx 2）和NAD（P）H：醌氧化还原酶（NQO 1）表达。在Nrf 2（+/+）小鼠中，发现高氧对肺Gpx 2和NQO 1的显著诱导高于室内空气对照。相比之下，Nrf 2（-/-）小鼠在高氧下对肺Gpx 2和NQO 1的诱导最小。还测量了不受Nrf 2调节的基因p21和IL-6的表达。与Nrf 2（+/+）小鼠相比，Nrf 2（-/-）小鼠肺组织中IL-6的表达在高氧72 h后明显增加。高氧可诱导Nrf 2（+/+）和Nrf 2（-/-）肺组织中p21的表达。与Nrf 2（+/+）小鼠相比，14日龄Nrf 2（-/-）小鼠的平均线性截距（MLI）和平均弦长（MCL）显著增加。新生儿高氧暴露14 d龄Nrf 2（-/-）小鼠肺泡表面活性蛋白C（Sp-c（+））2型细胞百分比也显著低于Nrf 2（-/-）小鼠（P < 0.02）。总之，这些研究结果表明，Nrf 2增加了新生小鼠暴露于高氧的存活率，Nrf 2可能有助于减弱高氧暴露引起的肺泡生长抑制。
McGrath-Morrow S, Lauer T, Yee M, Neptune E, Podowski M, Thimmulappa RK, O'Reilly M, Biswal S. Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol 296: L565-L573, 2009. First published January 16, 2009; doi: 10.1152/ajplung.90487.2008. Increased oxidative stress is associated with perinatal asphyxia and respiratory distress in the newborn period. Induction of nuclear factor erythroid 2 p45-related factor (Nrf2) has been shown to decrease oxidative stress through the regulation of specific gene pathways. We hypothesized that Nrf2 attenuates mortality and alveolar growth inhibition in newborn mice exposed to hyperoxia. Nrf2(+/+) and Nrf2(-/-) newborn mice were exposed to hyperoxia at 24 h. Survival was significantly less in Nrf2(-/-) mice exposed to 72 h of hyperoxia and returned to room air (P < 0.0001) and in Nrf2(-/-) mice exposed to hyperoxia for 8 continuous days (P < 0.005). To determine the response of Nrf2 target genes to hyperoxia, glutathione peroxidase 2 (Gpx2) and NAD(P) H: quinone oxidoreductase (NQO1) expression was measured from lung of newborn mice using real-time PCR. In the Nrf2(+/+) mice, significant induction of lung Gpx2 and NQO1 above room air controls was found with hyperoxia. In contrast, Nrf2(-/-) mice had minimal induction of lung Gpx2 and NQO1 with hyperoxia. Expression of p21 and IL-6, genes not regulated by Nrf2, were also measured. IL-6 expression in Nrf2(-/-) lung was markedly induced by 72 h of hyperoxia in contrast to the Nrf2(+/+) mice. p21 was induced in both Nrf2(+/+) and Nrf2(-/-) lung by hyperoxia. Mean linear intercept (MLI) and mean chord length (MCL) were significantly increased in 14-day-old Nrf2(-/-) mice previously exposed to hyperoxia compared with Nrf2(+/+) mice. The percentage of surfactant protein C (Sp-c(+)) type 2 alveolar cells in 14-day-old Nrf2(-/-) mice exposed to neonatal hyperoxia was also significantly less than Nrf2(-/-) mice (P < 0.02). In summary, these findings indicate that Nrf2 increases survival in newborn mice exposed to hyperoxia and that Nrf2 may help attenuate alveolar growth inhibition caused by hyperoxia exposure.