(-)-Epicatechin ameliorates cigarette smoke-induced lung inflammation via inhibiting ROS/NLRP3 inflammasome pathway in rats with COPD
(-)-Epicatechin ameliorates cigarette smoke-induced lung inflammation via inhibiting ROS/NLRP3 inflammasome pathway in rats with COPD
复制标题
(-)-表儿茶素通过抑制 ROS/NLRP3 炎症小体通路改善慢性阻塞性肺病 (COPD) 大鼠吸烟引起的肺部炎症
DOI：
10.1016/j.taap.2021.115674
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发表时间：
2021
影响因子：
3.8
通讯作者：
Zhang Min
中科院分区：
文献类型：
--
作者：
Tian Xue;Xue Yishu;Xie Guogang;Zhou Yan;Xiao Hui;Ding Fengming;Zhang Min
随着慢性阻塞性肺疾病(COPD)发病率和死亡率的增加，与吸烟(CS)密切相关的世界性医疗挑战。目前，还没有有效的治疗策略来控制COPD患者的炎症。本研究探讨了黄酮类化合物(−)-表儿茶素(EC)对CS诱导的慢性阻塞性肺疾病的保护作用及其机制。此外，在香烟烟雾提取物(CSE)治疗后，EC抑制了活性氧(ROS)的产生，并提高了人支气管上皮细胞的活力。进一步的研究表明，EC通过上调含三方基序的蛋白25(TRIM25)的表达促进泛素介导的Keap1降解，并增强Nrf2蛋白的核定位。EC还显著抑制NLRP3炎性小体的激活，减少CSE诱导的下垂，表现为减少乳酸脱氢酶的释放和caspase-1阳性细胞的数量。重要的是，Nrf2基因敲除至少部分逆转了EC对人支气管上皮细胞的保护作用。与体外实验结果一致，EC抑制NLRP3炎症小体的激活，减轻CS诱导的肺部炎症，表现为IL-1β和IL-18分泌减少。综上所述，本研究揭示了EC对实验性COPD大鼠的保护作用，阐明了EC促进Nrf2活性的机制，为COPD的治疗提供了新的策略。
Chronic obstructive pulmonary disease (COPD) with increased morbidity and mortality is a worldwide healthcare challenge closely associated with cigarette smoking (CS). Currently, there is no effective therapeutic strategy to control inflammation in COPD patients. The present study tested the protective effects of (−)-Epicatechin (EC), a type of flavonoid, on CS-induced COPD and the underlying mechanism. Also, EC repressed the production of reactive oxygen species (ROS) and improved human bronchial epithelial cell viability after cigarette smoke extract (CSE) treatment. Further studies demonstrated that EC promotes ubiquitin-mediated Keap1 degradation by upregulating tripartite motif-containing protein 25 (TRIM25) expression and enhances the nuclear localization of Nrf2 protein. Also, EC dramatically inhibits the activation of NLRP3 inflammasome and reduces the CSE-induced pyroptosis, as indicated by decreasing lactate dehydrogenase release and the number of caspase-1-positive cells. Importantly, Nrf2 knockdown reversed the protective effect of EC on human bronchial epithelial cells, at least partially. Consistent with the results in vitro, EC inhibits the activation of NLRP3 inflammasome and relieves the CS-induced lung inflammation, as evident from decreased interleukin (IL)-1β and IL-18 secretion in a COPD rat model. In conclusion, this study revealed the protective effect of EC on experimental COPD rats and elucidated the mechanism of EC promoting Nrf2 activity, which might provide a novel therapeutic strategy for COPD.