ROS induced the Rab26 promoter hypermethylation to promote cigarette smoking-induced airway epithelial inflammation of COPD through activation of MAPK signaling
ROS induced the Rab26 promoter hypermethylation to promote cigarette smoking-induced airway epithelial inflammation of COPD through activation of MAPK signaling
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DOI：
10.1016/j.freeradbiomed.2023.01.001
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发表时间：
2023-01-09
影响因子：
7.4
通讯作者：
Zhang, Jing
中科院分区：
文献类型：
--
作者：
He, Bin-feng;Wu, Yi-xing;Zhang, Jing
吸烟（CS）引起的气道炎症反应驱动肺气肿和慢性阻塞性肺疾病（COPD）的发生和发展。然而，其确切的机制尚未完全阐明。本研究旨在探讨Rab 26在CS暴露调节气道上皮炎症反应中的作用及其调控机制。这些数据表明，CS暴露和H2 O2（一种ROS）在体内和体外抑制Rab 26的表达，并增加DNMT 3b的表达。GEO数据分析发现COPD患者肺组织Rab 26水平降低。CSE诱导的ROS促进Rab 26启动子的DNA甲基化，并通过升高DNMT 3b水平抑制其启动子活性。抗氧化剂N-乙酰-L-半胱氨酸（NAC）、DNA甲基化抑制剂5-氮杂-2 '-脱氧胞苷（5-AZA）和DNMT 3B siRNA可减轻CSE对Rab 26表达的抑制作用。重要的是，NAC减轻了吸烟暴露气道中Rab 26表达的提高和DNMT 3B表达的降低，以及减轻了体内炎症反应。Rab 26过表达通过部分失活p38和JNK MAPK减弱CSE诱导的炎症介质产生。相反，沉默Rab 26可增强p38和JNK的激活，加重炎症反应。这些发现表明ROS介导的Rab 26启动子高甲基化是吸烟诱导的气道上皮炎症反应的关键步骤。修复气道上皮细胞Rab 26可能是治疗气道炎症和COPD的潜在策略。
Cigarette smoking (CS) exposure-induced airway inflammatory responses drive the occurrence and development of emphysema and chronic obstructive pulmonary disease (COPD). However, its precise mechanisms have not been fully elucidated. In this study, we explore the role of Rab26 in CS exposure modulating the inflammatory response of airway epithelium and the novel mechanism of CS exposure regulation Rab26. These data showed that CS exposure and H2O2 (a type of ROS) suppressed the expression of Rab26 and increased the expression of DNMT3b in vivo andin vitro. GEO data analysis found the level of Rab26 was decreased in the lung tissue of COPD patients. CSE-induced ROS promoted DNA methylation of the Rab26 promoter and inhibited its promoter activity by elevating the DNMT3b level. Antioxidants N-Acetyl-L-cysteine (NAC), 5-Aza-2 '-deoxycytidine (5-AZA) (DNA methylation inhibitor) and DNMT3B siRNA alleviated CSE's inhibitory effect on Rab26 expression in vitro. Importantly, NAC alleviated the improved expression of Rab26 and reduced DNMT3B expression, in the airway of smoking exposure as well as attenuated the inflammatory response in vivo. Overexpression of Rab26 atten-uated CSE-induced production of inflammatory mediators through part inactivation of p38 and JNK MAPK. On the contrary, silencing Rab26 enhanced p38 and JNK activation and aggravated inflammatory response. These findings suggest that ROS-mediated Rab26 promoter hypermethylation is a critical step in cigarette smoking-induced airway epithelial inflammatory response. Restoring Rab26 in the airway epithelium might be a po-tential strategy for treating airway inflammation and COPD.