TY - JOUR
T1 - Newborn mice lacking the gene for Cyp1a1 are more susceptible to oxygen-mediated lung injury, and are rescued by postnatal b-naphthoflavone administration
T2 - Implications for bronchopulmonary dysplasia in premature infants
AU - Maturu, Paramahamsa
AU - Wei-Liang, Yanhong
AU - Jiang, Weiwu
AU - Wang, Lihua
AU - Lingappan, Krithika
AU - Barrios, Roberto
AU - Liang, Yao
AU - Moorthy, Bhagavatula
AU - Couroucli, Xanthi I.
N1 - Funding Information:
We thank Dr Vijay Thakur for his help with the chromatin immunoprecipitation assays reported in this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. National Institutes of Health (R01HL088343 to X.C., K08-HL-127103 to K.L. and R01 grants ES-019689, ES-001932, HL-129794, and HL-112516 to B.M.).
Publisher Copyright:
© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Prolonged hyperoxia contributes to bronchopulmonary dysplasia (BPD) in preterm infants. b-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% 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.
AB - Prolonged hyperoxia contributes to bronchopulmonary dysplasia (BPD) in preterm infants. b-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% 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.
KW - B-naphthoflavone
KW - Bronchopulmonary dysplasia
KW - Cytochrome P4501A1
KW - Lung
KW - Newborn
KW - Oxidative injury
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U2 - 10.1093/toxsci/kfx036
DO - 10.1093/toxsci/kfx036
M3 - Article
C2 - 28201809
AN - SCOPUS:85020136698
SN - 1096-6080
VL - 157
SP - 260
EP - 271
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -