Zhu Xianying, Zhan Yuan, Gu Yiya, Huang Qian, Wang Ting, Deng Zhesong, Xie Jungang
Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Intensive Care Unit, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Front Physiol. 2021 Oct 8;12:733650. doi: 10.3389/fphys.2021.733650. eCollection 2021.
Chronic obstructive pulmonary disease (COPD), primarily attributed to cigarette smoke (CS), is characterized by multiple pathophysiological changes, including oxidative stress and inflammation. Stromal interaction molecule 1 (STIM1) is a Ca sensor that regulates Ca entry in different types of cells. The present study aimed to explore the relationship between CS-induced oxidative stress and inflammation, as well as the functional role of STIM1 thereinto. Our results showed that the reactive oxygen species (ROS)/STIM1/Ca axis played a critical role in CS-induced secretion of interleukin (IL)-8 in human alveolar macrophages. Specifically, smokers with COPD (SC) showed higher levels of ROS in the lung tissues compared with healthy non-smokers (HN). STIM1 was upregulated in the lung tissues of COPD patients. The expression of STIM1 was positively associated with ROS levels and negatively correlated with pulmonary function. The expression of STIM1 was also increased in the bronchoalveolar lavage fluid (BALF) macrophages of COPD patients and PMA-differentiated THP-1 macrophages stimulated by cigarette smoke extract (CSE). Additionally, CSE-induced upregulation of STIM1 in PMA-differentiated THP-1 macrophages was inhibited by pretreatment with N-acetylcysteine (NAC), a ROS scavenger. Transfection with small interfering RNA (siRNA) targeting STIM1 and pretreatment with NAC alleviated CSE-induced increase in intracellular Ca levels and IL-8 expression. Furthermore, pretreatment with SKF-96365 and 2-APB, the inhibitors of Ca influx, suppressed CSE-induced secretion of IL-8. In conclusion, our study demonstrates that CSE-induced ROS production may increase the expression of STIM1 in macrophages, which further promotes the release of IL-8 by regulating Ca entry. These data suggest that STIM1 may play a crucial role in CSE-induced ROS production and inflammation, and participate in the pathogenesis of COPD.
慢性阻塞性肺疾病（COPD）主要归因于香烟烟雾（CS），其特征是多种病理生理变化，包括氧化应激和炎症。基质相互作用分子1（STIM1）是一种钙传感器，可调节不同类型细胞中的钙内流。本研究旨在探讨CS诱导的氧化应激与炎症之间的关系，以及STIM1在其中的功能作用。我们的结果表明，活性氧（ROS）/STIM1/钙轴在CS诱导的人肺泡巨噬细胞中白细胞介素（IL）-8分泌中起关键作用。具体而言，与健康非吸烟者（HN）相比，慢性阻塞性肺疾病吸烟者（SC）肺组织中的ROS水平更高。COPD患者肺组织中STIM1上调。STIM1的表达与ROS水平呈正相关，与肺功能呈负相关。COPD患者支气管肺泡灌洗液（BALF）巨噬细胞和香烟烟雾提取物（CSE）刺激的佛波酯（PMA）分化的THP-1巨噬细胞中STIM1的表达也增加。此外，用活性氧清除剂N-乙酰半胱氨酸（NAC）预处理可抑制CSE诱导PMA分化的THP-1巨噬细胞中STIM1的上调。用靶向STIM1的小干扰RNA（siRNA）转染和用NAC预处理可减轻CSE诱导的细胞内钙水平升高和IL-8表达。此外，用钙内流抑制剂SKF-96365和2-氨基苯甲酸盐（2-APB）预处理可抑制CSE诱导的IL-8分泌。总之，我们的研究表明，CSE诱导的ROS产生可能增加巨噬细胞中STIMI的表达，进而通过调节钙内流促进IL-8的释放。这些数据表明，STIM1可能在CSE诱导的ROS产生和炎症中起关键作用，并参与COPD的发病机制。
