Newborn Mice Lacking the Gene for Cyp1a1 Are More Susceptible to Oxygen-Mediated Lung Injury, and Are Rescued by Postnatal β-Naphthoflavone Administration: Implications for Bronchopulmonary Dysplasia in Premature Infants
Newborn Mice Lacking the Gene for Cyp1a1 Are More Susceptible to Oxygen-Mediated Lung Injury, and Are Rescued by Postnatal β-Naphthoflavone Administration: Implications for Bronchopulmonary Dysplasia in Premature Infants
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DOI：
10.1093/toxsci/kfx036
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发表时间：
2017-05-01
影响因子：
3.8
通讯作者：
Couroucli, Xanthi I.
中科院分区：
文献类型：
--
作者：
Maturu, Paramahamsa;Wei-Liang, Yanhong;Couroucli, Xanthi I.
长期高氧会导致早产儿支气管肺发育不良（BPD）。 beta-Naphthoflavone (BNF) 是细胞色素 P450 (CYP) 1A 酶的有效诱导剂，该酶与成年小鼠的高氧损伤有关。在这项研究中，我们测试了这样的假设：缺乏 Cyp1a1 基因的新生小鼠比野生型 (WT) 小鼠更容易受到高氧性肺损伤，并且出生后 BNF 治疗将通过涉及 CYP1A 和/或 NAD(P)H 醌氧化还原酶 (NQO1) 酶的机制来挽救这种表型。新生WT或Cyp1a1缺失小鼠从出生后第2天到第14天，每隔一天用BNF（10mg/kg）或载体玉米油（CO）腹腔注射治疗，同时在室内空气或高氧（85％O-2）中维持14天。两种基因型均在高氧条件下表现出肺损伤、炎症和肺泡简化，与 WT 小鼠相比，Cyp1a1 缺失小鼠表现出更高的易感性。 BNF 治疗可显着减轻肺损伤和炎症，并改善 WT 和 Cyp1a1 缺失小鼠的肺泡化。与载体对照相比，BNF 暴露的常氧或高氧 WT 小鼠在 mRNA 和蛋白质水平上表现出肝脏 CYP1A1/1A2、肺 CYP1A1 和 NQO1 表达增加。然而，BNF 在 Cyp1a1 缺失小鼠中引起更大的肝脏 CYP1A2 和肺部 NQO1 酶诱导，表明 BNF 通过诱导 CYP1A 和 NQO1 酶来保护 WT 和 Cyp1a1 缺失小鼠免受高氧性肺损伤。关于类黄酮对新生儿高氧性肺损伤的保护作用的进一步研究可能会产生预防和/或治疗 BPD 的新策略。
Prolonged hyperoxia contributes to bronchopulmonary dysplasia (BPD) in preterm infants. beta-Naphthoflavone (BNF) is a potent inducer of cytochrome P450 (CYP) 1A enzymes, which have been implicated in hyperoxic injuries in adult mice. In this investigation, we tested the hypothesis that newborn mice lacking the Cyp1a1 gene would be more susceptible to hyperoxic lung injury than wild-type (WT) mice and that postnatal BNF treatment would rescue this phenotype by mechanisms involving CYP1A and/or NAD(P)H quinone oxidoreductase (NQO1) enzymes. Newborn WT or Cyp1a1-null mice were treated with BNF (10mg/kg) or the vehicle corn oil (CO) i.p., from postnatal day (PND) 2 to 14 once every other day, while being maintained in room air or hyperoxia (85% O-2) for 14 days. Both genotypes showed lung injury, inflammation, and alveolar simplification in hyperoxia, with Cyp1a1-null mice displaying increased susceptibility compared to WT mice. BNF treatment resulted in significant attenuation of lung injury and inflammation, with improved alveolarization in both WT and Cyp1a1-null mice. BNF exposed normoxic or hyperoxic WT mice showed increased expression of hepatic CYP1A1/1A2, pulmonary CYP1A1, and NQO1 expression at both mRNA and protein levels, compared with vehicle controls. However, BNF caused greater induction of hepatic CYP1A2 and pulmonary NQO1 enzymes in the Cyp1a1-null mice, suggesting that BNF protects against hyperoxic lung injury in WT and Cyp1a1-null mice through the induction of CYP1A and NQO1 enzymes. Further studies on the protective role of flavonoids against hyperoxic lung injury in newborns could lead to novel strategies for the prevention and/or treatment of BPD.