Nrf2 protects against airway disorders
Nrf2 protects against airway disorders
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DOI：
10.1016/j.taap.2009.07.024
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Kleeberger, Steven R.
中科院分区：
文献类型：
--
作者：
Cho, Hye-Youn;Kleeberger, Steven R.
核因子-红细胞2相关因子2（Nuclear factor-erythroid 2 related factor 2，Nrf 2）是一种广泛存在的转录因子，调节抗氧化反应元件（antioxidant response elements，战神）介导的抗氧化酶和细胞保护蛋白的表达。在非应激条件下，Kelch样ECH相关蛋白1（Keap 1）抑制细胞质中的细胞Nrf 2并驱动其蛋白酶体降解。nrf 2可以被多种刺激激活，包括氧化剂、促氧化剂、抗氧化剂和化学预防剂。nrf 2诱导细胞拯救途径对抗氧化损伤、异常炎症和免疫反应、细胞凋亡和致癌作用。Nrf 2种系突变小鼠的应用已经确定了Nrf 2在肝脏、胃肠道、气道、肾脏、脑、循环和免疫或神经系统的人类疾病实验模型中的广泛保护作用。在肺中，Nrf 2的缺乏加剧了由多种氧化损伤引起的毒性，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、细菌内毒素和其它炎症因子（例如，角叉菜胶），环境污染（例如，颗粒）和纤维化剂博来霉素。微阵列分析和生物信息学研究阐明了功能性战神和Nrf 2定向基因，它们是Nrf 2肺保护信号传导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队列中发现了NRF 2启动子多态性或KEAP 1和NRF 2体细胞和表观遗传突变与功能丧失的相关性，这进一步支持了NRF 2在这些肺部疾病中的作用。在当前的综述中，我们基于实验性氧化性疾病模型和人体研究的新证据，讨论了Nrf 2在气道中的作用。爱思唯尔公司出版
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, air-way, 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. Published by Elsevier Inc.