Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Building 101, MD D-201, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
Toxicol Appl Pharmacol. 2010 Apr 1;244(1):43-56. doi: 10.1016/j.taap.2009.07.024. Epub 2009 Jul 29.
Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a ubiquitous master transcription factor that regulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. In the unstressed condition, Kelch-like ECH-associated protein 1 (Keap1) suppresses cellular Nrf2 in cytoplasm and drives its proteasomal degradation. Nrf2 can be activated by diverse stimuli including oxidants, pro-oxidants, antioxidants, and chemopreventive agents. Nrf2 induces cellular rescue pathways against oxidative injury, abnormal inflammatory and immune responses, apoptosis, and carcinogenesis. Application of Nrf2 germ-line mutant mice has identified an extensive range of protective roles for Nrf2 in experimental models of human disorders in the liver, gastrointestinal tract, airway, kidney, brain, circulation, and immune or nerve system. In the lung, lack of Nrf2 exacerbated toxicity caused by multiple oxidative insults including supplemental respiratory therapy (e.g., hyperoxia, mechanical ventilation), cigarette smoke, allergen, virus, bacterial endotoxin and other inflammatory agents (e.g., carrageenin), environmental pollution (e.g., particles), and a fibrotic agent bleomycin. Microarray analyses and bioinformatic studies elucidated functional AREs and Nrf2-directed genes that are critical components of signaling mechanisms in pulmonary protection by Nrf2. Association of loss of function with promoter polymorphisms in NRF2 or somatic and epigenetic mutations in KEAP1 and NRF2 has been found in cohorts of patients with acute lung injury/acute respiratory distress syndrome or lung cancer, which further supports the role for NRF2 in these lung diseases. In the current review, we address the role of Nrf2 in airways based on emerging evidence from experimental oxidative disease models and human studies.
核因子红细胞 2 相关因子 2（Nrf2）是一种普遍存在的转录因子，可调节抗氧化反应元件（AREs）介导的抗氧化酶和细胞保护蛋白的表达。在未受应激的条件下，Kelch 样 ECH 相关蛋白 1（Keap1）抑制细胞质中的细胞 Nrf2，并促使其进行蛋白酶体降解。Nrf2 可以被多种刺激物激活，包括氧化剂、促氧化剂、抗氧化剂和化学预防剂。Nrf2 诱导细胞对抗氧化损伤、异常炎症和免疫反应、细胞凋亡和癌变的细胞保护途径。应用 Nrf2 种系突变小鼠已经确定了 Nrf2 在人类肝脏、胃肠道、气道、肾脏、大脑、循环以及免疫或神经系统疾病的实验模型中的广泛保护作用。在肺部，缺乏 Nrf2 会加剧多种氧化应激引起的毒性，包括补充呼吸治疗（例如，高氧、机械通气）、香烟烟雾、过敏原、病毒、细菌内毒素和其他炎症剂（例如，角叉菜胶）、环境污染（例如，颗粒）和纤维化剂博莱霉素。微阵列分析和生物信息学研究阐明了功能 AREs 和 Nrf2 指导的基因，它们是 Nrf2 介导的肺保护信号机制的关键组成部分。在急性肺损伤/急性呼吸窘迫综合征或肺癌患者的队列中，已经发现了 NRF2 或 KEAP1 和 NRF2 的启动子多态性与功能丧失的关联，以及体细胞和表观遗传突变，这进一步支持了 NRF2 在这些肺部疾病中的作用。在当前的综述中，我们根据实验氧化疾病模型和人类研究的新证据，探讨了 Nrf2 在气道中的作用。
