title: Targeted deletion of nrf2 impairs lung development and oxidant injury in neonatal mice.
abstract: OBJECTIVE
  Nrf2 is an essential transcription factor for protection against oxidant disorders. However, its role in organ development and neonatal disease has received little attention. Therapeutically administered oxygen has been considered to contribute to bronchopulmonary dysplasia (BPD) in prematurity. The current study was performed to determine Nrf2-mediated molecular events during saccular-to-alveolar lung maturation, and the role of Nrf2 in the pathogenesis of hyperoxic lung injury using newborn Nrf2-deficient (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice.
  
  
  RESULTS
  Pulmonary basal expression of cell cycle, redox balance, and lipid/carbohydrate metabolism genes was lower while lymphocyte immunity genes were more highly expressed in Nrf2(-/-) neonates than in Nrf2(+/+) neonates. Hyperoxia-induced phenotypes, including mortality, arrest of saccular-to-alveolar transition, and lung edema, and inflammation accompanying DNA damage and tissue oxidation were significantly more severe in Nrf2(-/-) neonates than in Nrf2(+/+) neonates. During lung injury pathogenesis, Nrf2 orchestrated expression of lung genes involved in organ injury and morphology, cellular growth/proliferation, vasculature development, immune response, and cell-cell interaction. Bioinformatic identification of Nrf2 binding motifs and augmented hyperoxia-induced inflammation in genetically deficient neonates supported Gpx2 and Marco as Nrf2 effectors.
  
  
  METHODS
  This investigation used lung transcriptomics and gene targeted mice to identify novel molecular events during saccular-to-alveolar stage transition and to elucidate Nrf2 downstream mechanisms in protection from hyperoxia-induced injury in neonate mouse lungs.
  
  
  CONCLUSIONS
  Nrf2 deficiency augmented lung injury and arrest of alveolarization caused by hyperoxia during the newborn period. Results suggest a therapeutic potential of specific Nrf2 activators for oxidative stress-associated neonatal disorders including BPD.
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. cho2@niehs.nih.gov
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Cho
authors.forename: Bennett
authors.initials: B
authors.lastname: van Houten
authors.forename: Xuting
authors.initials: X
authors.lastname: Wang
authors.forename: Laura
authors.initials: L
authors.lastname: Miller-DeGraff
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fostel
authors.forename: Wesley
authors.initials: W
authors.lastname: Gladwell
authors.forename: Ligon
authors.initials: L
authors.lastname: Perrow
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Panduri
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bell
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017353:Gene Deletion; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism*; D008168:Lung / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase