β-Naphthoflavone treatment attenuates neonatal hyperoxic lung injury in wild type and Cyp1a2-knockout mice

Abstract

Exposure to supraphysiological concentrations of oxygen (hyperoxia) leads to bronchopulmonary dysplasia (BPD), one of the most common pulmonary morbidities in preterm neonates, which is more prevalent in males than females. Beta-naphthoflavone (BNF) is protective against hyperoxic lung injury in adult and neonatal wild type (WT) mice and in and mice lacking Cyp1a1gene. In this investigation, we tested the hypothesis that BNF treatment will attenuate neonatal hyperoxic lung injury in WT and Cyp1a2-/- mice, and elucidated the effect of sex-specific differences. Newborn WT or Cyp1a2-/- mice were treated with BNF (10mg/kg) or the vehicle corn oil (CO) i.p., from postnatal day (PND) 2 to 8 once every other day, while being maintained in room air or hyperoxia (85% O2) for 14days. Hyperoxia exposure lead to alveolar simplification and arrest in angiogenesis in WT as well as Cyp1a2-/- mice No significant differences were seen between WT and Cyp1a2-/- mice. Cyp1a2-/- female mice had better preservation of pulmonary angiogenesis at PND15 compared to similarly exposed males. BNF treatment attenuated lung injury and inflammation in both genotypes, and this was accompanied by a significant induction of hepatic and pulmonary CYP1A1 in WT but not in Cyp1a2-/- mice. BNF treatment increased NADPH quinone oxidoreductase (NQO1) mRNA levels in Cyp1a2-/- mouse livers compared to WT mice. These results suggest that BNF is protective in neonatal mice exposed to hyperoxia independent of CYP1A2 and this may entail the protective effect of phase II enzymes like NQO1.

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

“…In contrast to the expectations, the severity of lung injury was not augmented in CYP1A2-knockout mice, suggesting a selective protective role for CYP1A1, but not CYP1A2. Again, the application of β-naphthoflavone in CYP1A2-knockout mice revealed that its action is mainly mediated by the NAD(P)H quinone oxidoreductase [32]. These data constitute further documentation of important differences in biological pathways between newborns and adults, which account for the disparities in hyperoxic lung injury.…”

“…Nrf2 is the key activator of the antioxidant stress response that includes NAD(P)H quinone oxidoreductase. Therefore, its dominant antioxidative role-which was demonstrated in NAD(P)H-quinone-oxidoreductase-knockout mice, and by the sustainable upregulation of β-naphthoflavone that prevented the features of hyperoxic lung injury-is not surprising [32,37].…”

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

“…In 2003, Cyp1a2 (-/-) mice were used to study the effect of CYP1A2 on insulin action and lipids biosynthetic pathways (Smith et al, 2003). The same model was also used to study the association between CYP1A2 deficiency and neonatal death, as well as respiratory distress syndrome (Pineau et al, 1995;Lingappan et al, 2018). Moreover, this model has been used to monitor the metabolic processes of procarcinogens and teratogens in vivo (Snyderwine et al, 2002;Nebert et al, 2004).…”

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

“…The alveolarization of newborn mice lacking cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1) is more susceptible to oxygen injury (360), suggesting an important protective effect of Cyp1a1 in antioxidant defense against hyperoxic injury. Along these lines, treatment of newborn mice with ␤-naphthoflavone-a potent inducer of the CYP family of detoxification enzymes of which Cyp1a1 is one-attenuated the stunted alveolarization provoked by hyperoxia in both wild-type mice (329), as well as Cyp1a1 Ϫ/Ϫ (360) and Cyp1a2 Ϫ/Ϫ mice (329).…”