Cho Hye-Youn, Reddy Sekhar P, Debiase Andrea, Yamamoto Masayuki, Kleeberger Steven R
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Free Radic Biol Med. 2005 Feb 1;38(3):325-43. doi: 10.1016/j.freeradbiomed.2004.10.013.
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.
核因子E2 p45相关因子2（NRF2）通过抗氧化/解毒酶的转录激活作用，对细胞起到保护作用，使其免受氧化损伤和化学致癌物的侵害。为了了解NRF2介导的对氧化性肺损伤保护作用的分子基础，我们对暴露于高氧环境或空气中的Nrf2基因敲除（Nrf2(-/-)）小鼠和野生型（Nrf2(+/+)）小鼠的肺脏基因表达谱进行了表征。在Nrf2(+/+)小鼠中组成性表达水平高于Nrf2(-/-)小鼠的基因包括抗氧化防御酶和免疫细胞受体基因。相对于Nrf2(+/+)小鼠，在Nrf2(-/-)小鼠中检测到热休克蛋白和结构基因的基础表达水平更高。在野生型小鼠中，高氧环境增强了175个基因（≥两倍）的表达，并降低了100个基因（≥50%）的表达。高氧诱导的许多知名/新的抗氧化/防御基因（如Txnrd1、Ex、Cp-2）和其他新基因（如Pkc-α、Tcf-3、Ppar-γ）的上调在Nrf2(+/+)小鼠中比在Nrf2(-/-)小鼠中明显更强。相反，编码细胞外基质和细胞骨架蛋白的基因在Nrf2(-/-)小鼠中的诱导表达高于Nrf2(+/+)小鼠。这些依赖NRF2的基因产物可能在预防高氧性肺损伤中起关键作用。我们的全基因组表达谱结果提供了氧组织毒性的假定下游分子机制。
