Prenatal administration of the cytochrome P4501A inducer, Β-naphthoflavone (BNF), attenuates hyperoxic lung injury in newborn mice: Implications for bronchopulmonary dysplasia (BPD) in premature infants

Abstract

Supplemental oxygen contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this investigation, we tested the hypothesis that prenatal treatment of pregnant mice (C57BL/6J) with the cytochrome P450 (CYP)1A1 inducer, β-napthoflavone (BNF), will lead to attenuation of lung injury in newborns (delivered from these dams) exposed to hyperoxia by mechanisms entailing transplacental induction of hepatic and pulmonary CYP1A enzymes. Pregnant mice were administered the vehicle corn oil (CO) or BNF (40 mg/kg), i.p., once daily for 3 days on gestational days (17–19), and newborns delivered from the mothers were either maintained in room air or exposed to hyperoxia (> 95% O2) for 1–5 days. After 3–5 days of hyperoxia, the lungs of CO-treated mice showed neutrophil infiltration, pulmonary edema, and perivascular inflammation. On the other hand, BNF-pretreated neonatal mice showed decreased susceptibility to hyperoxic lung injury. These mice displayed marked induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities, and levels of the corresponding apoproteins and mRNA levels until PND 3 in liver, while CYP1A1 expression alone was augmented in the lung. Prenatal BNF did not significantly alter gene expression of pulmonary NAD(P)H quinone reductase (NQO1). Hyperoxia for 24–72 h resulted in increased pulmonary levels of the F2-isoprostane 8-iso-PGF2α, whose levels were decreased in mice prenatally exposed to BNF. In conclusion, our results suggest that prenatal BNF protects newborns against hyperoxic lung injury, presumably by detoxification of lipid hydroperoxides by CYP1A enzymes, a phenomenon that has implications for prevention of BPD in infants.

Functional assessment of hyperoxia-induced lung injury after preterm birth in the rabbit

“…These results parallel those observed in other hyperoxic lung injury animal models (2,6,24,27,32) as well as what is clinically observed (16). These changes represent a lung developmental arrest, typically characterized by a simplification with enlarged alveoli and thickened septa (6,24,27,32).…”

Increased susceptibility to hyperoxic lung injury and alveolar simplification in newborn rats by prenatal administration of benzo[a]pyrene

“…Each sample was analyzed in duplicate. The relative Ct values for CYP1A1, 1A2 and CYP1B1 were normalized to their 18S content and the relative expression levels of target genes were calculated according to the equation, 2 −ΔΔCT , where ΔΔCT=ΔCt target gene−ΔCt control gene, as reported by us previously (Couroucli et al, 2006; 2011). …”

“…The molecular mechanisms by which hyperoxia causes lung injury are not understood, but CYP enzymes have been implicated (Hazinski et al, 1995). On the other hand, studies from our laboratory have demonstrated the protective effect of CYP1A enzymes against hyperoxic lung injury (Couroucli et al, 2011; Couroucli et al, 2002; Jiang et al, 2004; Moorthy et al, 2000; Sinha et al, 2005); Moorthy, 2008). However, there have been no studies on the effect of maternal exposure of environmental PAHs on hyperoxic lung injury in the offspring.…”

338: Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury

“…Furthermore, recent studies have demonstrated an attenuating effect of CYP1A1 inducers on hyperoxic lung injury both in vitro [10,24] as well as in vivo [11][12][13].…”

“…In recent years, the importance of cytochrome P450 enzymes as well as the aryl hydrocarbon receptor (AhR) has been demonstrated in the metabolism of a number of endogenous and exogenous compounds as well as for oxygen-induced toxicity [10][11][12][13]. When a ligand binds, AhR is translocated to the nucleus, where it dimerizes with the aryl hydrocarbon nuclear translocator (ARNT).…”