Gene expression profiling of NRF2-mediated protection against oxidative injury

Nuclear factor E2 p45-related factor 2 (NRF2) contributes to cellular protection against oxidative insults and chemical carcinogens via transcriptional activation of anitioxidant/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 (greater than or equal to twofold) and decreased expression of 100 genes (greater than or equal to50%) in wild-type mice. Hyperoxia-induced upregulation of many well-known/new antioxidant/defense genes (e.g. Txnrd 1, 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. (C) 2004 Elsevier Inc. All rights reserved.