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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeting Nrf2 With The Triterpenoid Cddo-imidazolide Attenuates Cigarette Smoke-induced Emphysema And Cardiac Dysfunction In Mice
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Targeting Nrf2 With The Triterpenoid Cddo-imidazolide Attenuates Cigarette Smoke-induced Emphysema And Cardiac Dysfunction In Mice

机译：用三萜类化合物Cddo-咪唑啉化物靶向Nrf2减轻香烟烟雾引起的肺气肿和小鼠心脏功能障碍

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Chronic obstructive pulmonary disease (COPD), which comprises emphysema and chronic bronchitis resulting from prolonged exposure to cigarette smoke (CS), is a major public health burden with no effective treatment. Emphysema is also associated with pulmonary hypertension, which can progress to right ventricular failure, an important cause of morbidity and mortality among patients with COPD. Nuclear erythroid 2 p45 related factor-2 (Nrf2) is a redox-sensitive transcription factor that up-regulates a battery of antioxidative genes and cytoprotective enzymes that constitute the defense against oxidative stress. Recently, it has been shown that patients with advanced COPD have a decline in expression of the Nrf2 pathway in lungs, suggesting that loss of this antioxidative protective response is a key factor in the pathophysiological progression of emphysema. Furthermore, genetic disruption of Nrf2 in mice causes early-onset and severe emphysema. The present study evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with a small molecule would attenuate CS-induced oxidative stress and emphysema. Nrf2~(+/+) and Nrf2~(-/-) mice were fed a diet containing the potent Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-lm), while being exposed to CS for 6 months. CDDO-lm significantly reduced lung oxidative stress, alveolar cell apoptosis, alveolar destruction, and pulmonary hypertension in Nrf2~(+/+) mice caused by chronic exposure to CS. This protection from CS-induced emphysema depended on Nrf2, as Nrf2~(-/-) mice failed to show significant reduction in alveolar cell apoptosis and alveolar destruction after treatment with CDDO-lm. These results suggest that targeting the Nrf2 pathway during the etiopathogenesis of emphysema may represent an important approach for prophylaxis against COPD.
机译：慢性阻塞性肺疾病（COPD）包括长期暴露于香烟烟雾（CS）引起的肺气肿和慢性支气管炎，是没有有效治疗的主要公共卫生负担。肺气肿也与肺动脉高压有关，肺动脉高压可发展为右心室衰竭，这是COPD患者发病和死亡的重要原因。核红细胞2 p45相关因子2（Nrf2）是氧化还原敏感的转录因子，它上调一系列抗氧化基因和细胞保护酶，从而构成抵抗氧化应激的防御作用。最近，已经表明，患有晚期COPD的患者肺中Nrf2途径的表达下降，表明该抗氧化保护反应的丧失是肺气肿的病理生理进展的关键因素。此外，Nrf2在小鼠中的遗传破坏会导致早期发作和严重的肺气肿。本研究评估了Nrf2的激活策略及其下游带有小分子的细胞保护基因的网络是否会减弱CS诱导的氧化应激和肺气肿。给Nrf2〜（+ / +）和Nrf2〜（-/-）小鼠喂食含有有效Nrf2激活剂1- [2-cyano-3-，12-dioxooleana-1,9（11）-dien-28的饮食-oyl]咪唑（CDDO-lm），同时接触CS 6个月。 CDDO-lm可显着降低Nrf2〜（+ / +）小鼠长期暴露于CS引起的肺氧化应激，肺泡细胞凋亡，肺泡破坏和肺动脉高压。 CS诱导的肺气肿的这种保护作用依赖于Nrf2，因为用CDDO-lm处理后，Nrf2〜（-/-）小鼠未能显示出肺泡细胞凋亡和肺泡破坏的显着减少。这些结果表明，在肺气肿的发病机理中靶向Nrf2途径可能是预防COPD的重要方法。

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