title: Gene expression profiling of NRF2-mediated protection against oxidative injury.
abstract: Nuclear factor E2 p45-related factor 2 (NRF2) contributes to cellular protection against oxidative insults and chemical carcinogens via transcriptional activation of antioxidant/detoxifying enzymes. To understand the molecular basis of NRF2-mediated protection against oxidative lung injury, pulmonary gene expression profiles were characterized in Nrf2-disrupted (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice exposed to hyperoxia or air. Genes expressed constitutively higher in Nrf2(+/+) mice than in Nrf2(-/-) mice included antioxidant defense enzyme and immune cell receptor genes. Higher basal expression of heat shock protein and structural genes was detected in Nrf2(-/-) mice relative to Nrf2(+/+) mice. Hyperoxia enhanced expression of 175 genes (> or = twofold) and decreased expression of 100 genes (> or =50%) in wild-type mice. Hyperoxia-induced upregulation of many well-known/new antioxidant/defense genes (e.g., Txnrd1, Ex, Cp-2) and other novel genes (e.g., Pkc-alpha, Tcf-3, Ppar-gamma) was markedly greater in Nrf2(+/+) mice than in Nrf2(-/-) mice. In contrast, induced expression of genes encoding extracellular matrix and cytoskeletal proteins was higher in Nrf2(-/-) mice than in Nrf2(+/+) mice. These NRF2-dependent gene products might have key roles in protection against hyperoxic lung injury. Results from our global gene expression profiles provide putative downstream molecular mechanisms of oxygen tissue toxicity.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. cho2@niehs.nih.gov
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Cho
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
authors.forename: Andrea
authors.initials: A
authors.lastname: Debiase
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001273:Atmosphere Exposure Chambers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008954:Models, Biological; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D010100:Oxygen