Hyperoxia-mediated transcriptional activation of cytochrome P4501A1 (CYP1A1) and decreased susceptibility to oxygen-mediated lung injury in newborn mice.
Hyperoxia-mediated transcriptional activation of cytochrome P4501A1 (CYP1A1) and decreased susceptibility to oxygen-mediated lung injury in newborn mice.
复制标题
高氧介导的细胞色素 P4501A1 (CYP1A1) 转录激活可降低新生小鼠对氧介导的肺损伤的易感性。
DOI：
10.1016/j.bbrc.2017.10.166
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发表时间：
2018
影响因子：
3.1
通讯作者：
Couroucli,Xanthi
中科院分区：
文献类型：
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作者：
Jiang,Weiwu;Maturu,Paramahamsa;Liang,YanhongWei;Wang,Lihua;Lingappan,Krithika;Couroucli,Xanthi
高氧有助于早产儿支气管肺发育不良（BPD）的发展。在这项研究中，我们测试了这样一个假设，即携带人CYP 1A 1-Luc启动子的新生转基因小鼠在体内暴露于高氧时会显示人CYP 1A 1启动子的转录激活，并且这些小鼠对高氧肺损伤和肺泡简化的敏感性低于类似暴露的野生型（WT）小鼠。将携带13.2 kb人CYP 1A 1启动子和荧光素酶（Luc）报告基因（CYP 1A 1-luc）的新生WT（CD-1）或转基因小鼠在室内空气中或暴露于高氧（85% O2）中7-14天。与室内空气对照相比，CYP 1A 1-Luc小鼠高氧暴露7天和14天分别导致肝脏Luc（CYP 1A 1）表达增加4倍和30倍。在肺中，高氧在第7天引起报告基因Luc的2倍诱导，但诱导在14天后下降。与暴露相似的野生型（WT）CD-1小鼠相比，新的CYP 1A 1-Luc小鼠对肺损伤和肺泡简化的敏感性较低。此外，CYP 1A 1-Luc小鼠在高氧暴露后表现出肝和肺CYP 1A 1表达水平和肝CYP 1A 2活性增加。高氧也增加了CD-1和CYP 1A 1-Luc小鼠在两个时间点的NADP（H）醌还原酶（NQO 1）肺基因表达，但后者在14天时更为明显。我们的结果支持了高氧激活新生小鼠CYP 1A 1启动子的假说，以及CYP 1A 1和NADP（H）醌还原酶（NQO 1）内源性表达的增加有助于降低转基因动物对高氧肺损伤的易感性。这是第一份报告提供证据的高氧介导的转录激活的humanCYP 1A 1启动子在新生小鼠，这与减少肺损伤，这表明，这些现象有重要意义的BPD。
Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this study, we tested the hypothesis that newborn transgenic mice carrying the humanCYP1A1-Luc promoter will display transcriptional activation of the humanCYP1A1promoterin vivoupon exposure to hyperoxia, and that these mice will be less susceptible to hyperoxic lung injury and alveolar simplification than similarly exposed wild type (WT) mice. Newborn WT (CD-1) or transgenic mice carrying a 13.2 kb humanCYP1A1promoter and the luciferase (Luc) reporter gene (CYP1A1-luc) were maintained in room air or exposed to hyperoxia (85% O2) for 7–14 days. Hyperoxia exposure ofCYP1A1-Luc mice for 7 and 14 days resulted in 4- and 30-fold increases, respectively, in hepatic Luc (CYP1A1) expression, compared to room air controls. In lung, hyperoxia caused a 2-fold induction of reporter Luc at 7 days, but the induction declined after 14 days. The newbornCYP1A1-Luc mice were less susceptible to lung injury and alveolar simplification than similarly exposed wild type (WT) CD-1 mice. Also, theCYP1A1-Luc mice showed increased levels of hepatic and pulmonary CYP1A1 expression and hepatic CYP1A2 activity after hyperoxia exposure. Hyperoxia also increased NADP(H) quinone reductase (NQO1) pulmonary gene expression in both CD-1 andCYP1A1-Luc mice at both time points, but this was more pronounced in the latter at 14 days. Our results support the hypothesis that hyperoxia activates the humanCYP1A1promoter in newborn mice, and that increased endogenous expression of CYP1A1 and NADP(H) quinone reductase (NQO1) contributes to the decreased susceptibilities to hyperoxic lung injury in the transgenic animals. This is the first report providing evidence of hyperoxia-mediated transcriptional activation of the humanCYP1A1promoter in newborn mice, and this in conjunction with decreased lung injury, suggests that these phenomena have important implications for BPD.