Role of NRF2 in protection against hyperoxic lung injury in mice.
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.
Cho
Hye-Youn
HY
Department of Environmental Health Sciences, The Bloomberg School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Jedlicka
Anne E
AE
Reddy
Sekhar P M
SP
Kensler
Thomas W
TW
Yamamoto
Masayuki
M
Zhang
Liu-Yi
LY
Kleeberger
Steven R
SR
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D016350:Leucine Zippers; D008168:Lung / Q000166:cytology / Q000201:enzymology* / Q000503:physiopathology; D055370:Lung Injury; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D014020:Tissue Extracts / Q000737:chemistry; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D000975:Antioxidants; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014020:Tissue Extracts; D015534:Trans-Activators; D010100:Oxygen