title: 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.
abstract: Prolonged hyperoxia contributes to bronchopulmonary dysplasia (BPD) in preterm infants. β-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 (10 mg/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% O2) 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.
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Paramahamsa
authors.initials: P
authors.lastname: Maturu
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wei-Liang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Weiwu
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Krithika
authors.initials: K
authors.lastname: Lingappan
authors.affiliation: Department of Pathology and Genomic Medicine, The Methodist Hospital Physician Organization, Houston, Texas, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Barrios
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xanthi I
authors.initials: XI
authors.lastname: Couroucli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001997:Bronchopulmonary Dysplasia / Q000209:etiology* / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000008:administration & dosage*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000201:enzymology; D019324:beta-Naphthoflavone / Q000008:administration & dosage*
chemical_list: D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D010100:Oxygen
keywords: bronchopulmonary dysplasia.; cytochrome P4501A1; lung; newborn; oxidative injury; β-naphthoflavone