Role of NRF2 in protection against hyperoxic lung injury in mice.

Abstract

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.

• Authors: Hye-Youn Cho, Anne E Jedlicka, Sekhar P M Reddy, Thomas W Kensler, Masayuki Yamamoto, Liu-Yi Zhang, Steven R Kleeberger
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 26 Issue 2 Pg. 175-82 (Feb 2002) ISSN: 1044-1549 [Print] United States
• PMID: 11804867 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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