The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis.
The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis.
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DOI：
10.1101/gad.237081.113
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发表时间：
2014-03-15
影响因子：
10.5
通讯作者：
Meng QJ
中科院分区：
文献类型：
--
作者：
Pekovic-Vaughan V;Gibbs J;Yoshitane H;Yang N;Pathiranage D;Guo B;Sagami A;Taguchi K;Bechtold D;Loudon A;Yamamoto M;Chan J;van der Horst GT;Fukada Y;Meng QJ
NRF2/谷胱甘肽介导的抗氧化防御通路的破坏对慢性肺部疾病的发病机制至关重要。在这里，Pekovic-Vaughan等人证明NRF2蛋白的昼夜节律在调节小鼠肺中抗氧化基因的节律性表达中是必不可少的。当博来霉素应用于NRF2水平的昼夜最低点时，观察到更严重的肺纤维化效应。这些发现揭示了NRF2途径的昼夜节律控制在对抗纤维化肺损伤中的关键作用。NRF2（核因子红细胞衍生2-样2）/谷胱甘肽介导的抗氧化防御途径的破坏是几种慢性肺部疾病和癌症发病的关键步骤。虽然NRF2在氧化应激中的激活机制已被广泛研究，但对调控NRF2通路在肺生理病理中的内源性信号知之甚少。本研究表明，e -box介导的NRF2蛋白昼夜节律对于调节小鼠肺中参与谷胱甘肽氧化还原稳态的抗氧化基因的节律性表达至关重要。利用体内博来霉素诱导的肺纤维化模型，我们揭示了对氧化损伤的时钟“门控”肺反应，当博来霉素在NRF2水平的昼夜最低点应用时，纤维化效果更严重。定时给药萝卜硫素（一种NRF2激活剂）可显著阻断这种表型。此外，在心律失常ClockΔ19小鼠的肺中，NRF2和还原性谷胱甘肽的水平构成性低，与蛋白质氧化损伤增加和自发纤维化样肺表型相关。我们的研究结果揭示了NRF2/谷胱甘肽途径的昼夜节律控制在对抗氧化/纤维化肺损伤中的关键作用，这可能为治疗人类肺部疾病（包括特发性肺纤维化）提供新的时间治疗策略。
Disruption of the NRF2/glutathione-mediated antioxidant defense pathway is critical for the pathogenesis of chronic pulmonary diseases. Here, Pekovic-Vaughan et al. demonstrate that a circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes in the mouse lung. When bleomycin was applied at a circadian nadir in NRF2 levels, a more severe lung fibrotic effect was observed. These findings reveal a crucial role for the circadian control of the NRF2 pathway in combating fibrotic lung damage. The disruption of the NRF2 (nuclear factor erythroid-derived 2-like 2)/glutathione-mediated antioxidant defense pathway is a critical step in the pathogenesis of several chronic pulmonary diseases and cancer. While the mechanism of NRF2 activation upon oxidative stress has been widely investigated, little is known about the endogenous signals that regulate the NRF2 pathway in lung physiology and pathology. Here we show that an E-box-mediated circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the mouse lung. Using an in vivo bleomycin-induced lung fibrosis model, we reveal a clock “gated” pulmonary response to oxidative injury, with a more severe fibrotic effect when bleomycin was applied at a circadian nadir in NRF2 levels. Timed administration of sulforaphane, an NRF2 activator, significantly blocked this phenotype. Moreover, in the lungs of the arrhythmic ClockΔ19 mice, the levels of NRF2 and the reduced glutathione are constitutively low, associated with increased protein oxidative damage and a spontaneous fibrotic-like pulmonary phenotype. Our findings reveal a pivotal role for the circadian control of the NRF2/glutathione pathway in combating oxidative/fibrotic lung damage, which might prompt new chronotherapeutic strategies for the treatment of human lung diseases, including idiopathic pulmonary fibrosis.
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