Jiang Weiwu, Maturu Paramahamsa, Liang Yanhong Wei, Wang Lihua, Lingappan Krithika, Couroucli Xanthi
Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030, USA.
Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030, USA.
Biochem Biophys Res Commun. 2018 Jan 1;495(1):408-413. doi: 10.1016/j.bbrc.2017.10.166. Epub 2017 Oct 31.
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 human CYP1A1-Luc promoter will display transcriptional activation of the human CYP1A1 promoter in vivo upon 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 human CYP1A1 promoter and the luciferase (Luc) reporter gene (CYP1A1-luc) were maintained in room air or exposed to hyperoxia (85% O) for 7-14 days. Hyperoxia exposure of CYP1A1-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 newborn CYP1A1-Luc mice were less susceptible to lung injury and alveolar simplification than similarly exposed wild type (WT) CD-1 mice. Also, the CYP1A1-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 and CYP1A1-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 human CYP1A1 promoter 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 human CYP1A1 promoter in newborn mice, and this in conjunction with decreased lung injury, suggests that these phenomena have important implications for BPD.
高氧血症会促使早产儿发生支气管肺发育不良（BPD）。在本研究中，我们验证了以下假设：携带人CYP1A1-Luc启动子的新生转基因小鼠在暴露于高氧环境后，体内人CYP1A1启动子会出现转录激活，并且与同样暴露于高氧环境的野生型（WT）小鼠相比，这些小鼠对高氧性肺损伤和肺泡简化的易感性更低。将新生WT（CD-1）小鼠或携带13.2 kb人CYP1A1启动子和荧光素酶（Luc）报告基因（CYP1A1-luc）的转基因小鼠置于室内空气中，或暴露于高氧环境（85% O₂）中7至14天。与室内空气对照组相比，CYP1A1-Luc小鼠暴露于高氧环境7天和14天后，肝脏Luc（CYP1A1）表达分别增加了4倍和30倍。在肺组织中，高氧在7天时导致报告基因Luc诱导增加2倍，但在14天后诱导作用下降。新生CYP1A1-Luc小鼠比同样暴露于高氧环境的野生型（WT）CD-1小鼠对肺损伤和肺泡简化的易感性更低。此外，CYP1A1-Luc小鼠在暴露于高氧环境后，肝脏和肺组织中CYP1A1表达水平以及肝脏CYP1A2活性均有所增加。在两个时间点，高氧均增加了CD-1小鼠和CYP1A1-Luc小鼠肺组织中NADP(H)醌还原酶（NQO1）基因的表达，但在14天时，后者更为明显。我们的结果支持以下假设：高氧可激活新生小鼠体内的人CYP1A1启动子，并且CYP1A1和NADP(H)醌还原酶（NQO1）内源性表达的增加有助于转基因动物对高氧性肺损伤易感性的降低。这是第一份提供证据表明高氧可介导新生小鼠体内人CYP1A1启动子转录激活的报告，并且这与肺损伤的减轻相关，表明这些现象对BPD具有重要意义。
