Wang Xinjing, Murugesan Priya, Zhang Pan, Xu Shiqing, Peng Liang, Wang Chen, Cai Hua
Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing 100069, China.
Department of Anesthesiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Antioxidants (Basel). 2022 Aug 8;11(8):1539. doi: 10.3390/antiox11081539.
Cigarette smoke (CS) is a major risk factor for chronic obstructive pulmonary disease (COPD), which represents the third leading cause of death worldwide. CS induces reactive oxygen species (ROS) production, leading to pulmonary inflammation and remodeling. NADPH oxidases (NOXs) represent essential sources of ROS production in the cardiovascular system. Whether and how NOX isoforms are activated in COPD patients and in response to acute cigarette smoke (ACS) remains incompletely understood. In the present study, the expression of NOX isoforms was examined in the lungs of end-stage COPD patients. In addition, mice silenced of NOX1 or NOX4 expression using in vivo RNA interference (RNAi), and NOX2-deficient (NOX2) mice, were exposed to ACS for 1 h using a standard TE-10B smoking machine. In lung sections isolated from COPD patients undergoing lung transplantation, protein expression of NOX1, NOX2, NOX4, or NOX5 was markedly upregulated compared to non-smoking donor controls. Likewise, ACS upregulated protein expression of NOX1, NOX2, and NOX4, production of ROS, inflammatory cell infiltration, and mRNA expression of proinflammatory cytokines TNF-α and KC in the mouse lung. In vivo RNAi knockdown of NOX1 or NOX4 decreased ACS induced ROS production, inflammatory cell influx, and the expression of TNF-α and KC, which were accompanied by inhibition of the NF-κB-COX-2 axis. Although ACS induced ROS production was reduced in the lungs of NOX2 mice, inflammatory cell influx and expression of NF-κB/COX-2 were increased. Taken together, our results demonstrate for the first time that NOX isoforms 1, 2, 4 and 5 all remain activated in end-stage COPD patients, while NOX1 and NOX4 mediate oxidative stress and inflammatory responses in response to acute cigarette smoke. Therefore, targeting different isoforms of NOX might be necessary to treat COPD at different stages of the disease, which represents novel mechanistic insights enabling improved management of the devastating disease.
香烟烟雾（CS）是慢性阻塞性肺疾病（COPD）的主要危险因素，COPD是全球第三大死因。CS诱导活性氧（ROS）生成，导致肺部炎症和重塑。NADPH氧化酶（NOXs）是心血管系统中ROS生成的重要来源。COPD患者以及急性香烟烟雾（ACS）刺激下NOX亚型是否被激活以及如何被激活，目前仍不完全清楚。在本研究中，检测了终末期COPD患者肺组织中NOX亚型的表达。此外，利用体内RNA干扰（RNAi）使NOX1或NOX4表达沉默的小鼠，以及NOX2基因敲除（NOX2-/-）小鼠，使用标准的TE-10B吸烟机暴露于ACS 1小时。在接受肺移植的COPD患者分离的肺组织切片中，与非吸烟供体对照相比，NOX1、NOX2、NOX4或NOX5的蛋白表达明显上调。同样，ACS上调了小鼠肺组织中NOX1、NOX2和NOX4的蛋白表达、ROS生成、炎性细胞浸润以及促炎细胞因子TNF-α和KC的mRNA表达。体内RNAi敲低NOX1或NOX4可降低ACS诱导的ROS生成、炎性细胞流入以及TNF-α和KC的表达，同时伴有NF-κB-COX-2轴的抑制。虽然ACS诱导的ROS生成在NOX2-/-小鼠肺组织中减少，但炎性细胞流入以及NF-κB/COX-2的表达增加。综上所述，我们的结果首次表明，NOX亚型1、2、4和5在终末期COPD患者中均保持激活状态，而NOX1和NOX4介导急性香烟烟雾刺激下的氧化应激和炎症反应。因此，针对不同的NOX亚型进行靶向治疗可能是治疗COPD不同阶段疾病所必需的，这为改善这种毁灭性疾病的管理提供了新的机制见解。
