Role of NRF2 in protection against hyperoxic lung injury in mice

Am J Respir Cell Mol Biol. 2002 Feb;26(2):175-82. doi: 10.1165/ajrcmb.26.2.4501.


NRF2 is a transcription factor important in the protection against carcinogenesis and oxidative stress through antioxidant response element (ARE)-mediated transcriptional activation of several phase 2 detoxifying and antioxidant enzymes. This study was designed to determine the role of NRF2 in the pathogenesis of hyperoxic lung injury by comparing pulmonary responses to 95-98% oxygen between mice with site-directed mutation of the gene for NRF2 (Nrf2-/-) and wild-type mice (Nrf2+/+). Pulmonary hyperpermeability, macrophage inflammation, and epithelial injury in Nrf2-/- mice were 7.6-fold, 47%, and 43% greater, respectively, compared with Nrf2+/+ mice after 72 h hyperoxia exposure. Hyperoxia markedly elevated the expression of NRF2 mRNA and DNA-binding activity of NRF2 in the lungs of Nrf2+/+ mice. mRNA expression for ARE- responsive lung antioxidant and phase 2 enzymes was evaluated in both genotypes of mice to identify potential downstream molecular mechanisms of NRF2 in hyperoxic lung responses. Hyperoxia-induced mRNA levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione-S-transferase (GST)-Ya and -Yc subunits, UDP glycosyl transferase (UGT), glutathione peroxidase-2 (GPx2), and heme oxygenase-1 (HO-1) were significantly lower in Nrf2-/- mice compared with Nrf2+/+ mice. Consistent with differential mRNA expression, NQO1 and total GST activities were significantly lower in Nrf2-/- mice compared with Nrf2+/+ mice after hyperoxia. Results demonstrated that NRF2 has a significant protective role against pulmonary hyperoxic injury in mice, possibly through transcriptional activation of lung antioxidant defense enzymes.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Bronchoalveolar Lavage Fluid / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epithelial Cells / metabolism
  • Gene Expression Regulation, Enzymologic / physiology*
  • Leucine Zippers
  • Lung / cytology
  • Lung / enzymology*
  • Lung / physiopathology
  • Lung Injury
  • Macrophages, Alveolar / metabolism
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oxidation-Reduction
  • Oxygen / toxicity*
  • RNA, Messenger / metabolism
  • Tissue Extracts / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*


  • Antioxidants
  • DNA-Binding Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Nuclear Proteins
  • RNA, Messenger
  • Tissue Extracts
  • Trans-Activators
  • Oxygen