Geraghty Patrick, Baumlin Nathalie, Salathe Matthias A, Foronjy Robert F, D'Armiento Jeanine M
Division of Pulmonary & Critical Care Medicine, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Miami, Miami, FL, USA.
Mediators Inflamm. 2016;2016:9461289. doi: 10.1155/2016/9461289. Epub 2016 Dec 13.
Oxidative stress provokes endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) in the lungs of chronic obstructive pulmonary (COPD) subjects. The antioxidant, glutathione peroxidase-1 (GPx-1), counters oxidative stress induced by cigarette smoke exposure. Here, we investigate whether GPx-1 expression deters the UPR following exposure to cigarette smoke. Expression of ER stress markers was investigated in fully differentiated normal human bronchial epithelial (NHBE) cells isolated from nonsmoking, smoking, and COPD donors and redifferentiated at the air liquid interface. NHBE cells from COPD donors expressed heightened ATF4, XBP1, GRP78, GRP94, EDEM1, and CHOP compared to cells from nonsmoking donors. These changes coincided with reduced GPx-1 expression. Reintroduction of GPx-1 into NHBE cells isolated from COPD donors reduced the UPR. To determine whether the loss of GPx-1 expression has a direct impact on these ER stress markers during smoke exposure, - mice were exposed to cigarette smoke for 1 year. Loss of - expression enhanced cigarette smoke-induced ER stress and apoptosis. Equally, induction of ER stress with tunicamycin enhanced antioxidant expression in mouse precision-cut lung slices. Smoke inhalation also exacerbated the UPR response during respiratory syncytial virus infection. Therefore, ER stress may be an antioxidant-related pathophysiological event in COPD.
氧化应激在慢性阻塞性肺疾病（COPD）患者的肺部引发内质网（ER）应激诱导的未折叠蛋白反应（UPR）。抗氧化剂谷胱甘肽过氧化物酶-1（GPx-1）可对抗香烟烟雾暴露诱导的氧化应激。在此，我们研究GPx-1表达是否能在暴露于香烟烟雾后抑制UPR。我们在从非吸烟、吸烟和COPD供体分离并在气液界面重新分化的完全分化的正常人支气管上皮（NHBE）细胞中研究了ER应激标志物的表达。与非吸烟供体的细胞相比，COPD供体的NHBE细胞中ATF4、XBP1、GRP78、GRP94、EDEM1和CHOP的表达升高。这些变化与GPx-1表达降低同时发生。将GPx-1重新导入从COPD供体分离的NHBE细胞中可降低UPR。为了确定GPx-1表达缺失在烟雾暴露期间是否对这些ER应激标志物有直接影响，将-小鼠暴露于香烟烟雾中1年。-表达缺失增强了香烟烟雾诱导的ER应激和细胞凋亡。同样，用衣霉素诱导ER应激可增强小鼠精密切割肺切片中的抗氧化剂表达。吸入烟雾也加剧了呼吸道合胞病毒感染期间的UPR反应。因此，ER应激可能是COPD中与抗氧化剂相关的病理生理事件。
