Department of Medicine, Divisions of Molecular and Pulmonary Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Int J Chron Obstruct Pulmon Dis. 2011;6:309-19. doi: 10.2147/COPD.S19599. Epub 2011 Jun 2.
Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease (COPD). Recent studies propose a link between endoplasmic reticulum (ER) stress and emphysema, demonstrated by increased ER stress markers under smoking conditions. Here, we investigate whether cigarette smoke-induced ER stress is cell specific and correlates with acute and chronic cigarette smoke exposure.
Gene and protein expression changes in human primary lung cell cultures following cigarette smoke extract (CSE) exposure were monitored by qPCR and Western blot analysis. Mice and guinea pigs were exposed to cigarette smoke and ER stress markers examined in whole lung homogenates. Inflammatory cells from the bronchoalveolar lavage fluid of 10 days smoke exposed mice were also examined.
Cigarette smoke induced a trend increase in the ER stress response through an activating transcription factor 4 (ATF4) mediated induction of C/EBP homologous protein (CHOP) in primary small airway epithelial cells. Bronchial epithelial cells and macrophages responded similarly to CSE. Wild-type mice and guinea pigs exposed to acute levels of cigarette smoke exhibited increased levels of CHOP but not at significant levels. However, after long-term chronic cigarette smoke exposure, CHOP expression was reduced. Interestingly, inflammatory cells from smoke exposed mice had a significant increase in CHOP/ATF4 expression.
A trend increase in CHOP levels appear in multiple human lung cell types following acute cigarette smoke exposure in vitro. In vivo, inflammatory cells, predominately macrophages, demonstrate significant cigarette smoke-induced ER stress. Early induction of CHOP in cigarette smoke may play a pivotal role in early induction of lung disease, however in vivo long-term cigarette smoke exposure exhibited a reduction in the ER stress response.
香烟烟雾是导致慢性阻塞性肺疾病（COPD）发展的主要危险因素。最近的研究提出内质网（ER）应激与肺气肿之间存在联系，在吸烟条件下 ER 应激标志物增加证明了这一点。在这里，我们研究香烟烟雾诱导的 ER 应激是否具有细胞特异性，并与急性和慢性香烟烟雾暴露相关。
通过 qPCR 和 Western blot 分析监测香烟烟雾提取物（CSE）暴露后人原代肺细胞培养物中的基因和蛋白表达变化。用香烟烟雾暴露小鼠和豚鼠，检查整个肺匀浆中的 ER 应激标志物。还检查了 10 天吸烟暴露小鼠支气管肺泡灌洗液中的炎症细胞。
香烟烟雾通过激活转录因子 4（ATF4）介导的 C/EBP 同源蛋白（CHOP）诱导，在原代小气道上皮细胞中引起 ER 应激反应的趋势增加。支气管上皮细胞和巨噬细胞对 CSE 的反应相似。暴露于急性水平香烟烟雾的野生型小鼠和豚鼠表现出 CHOP 水平增加，但没有达到显著水平。然而，长期慢性香烟烟雾暴露后，CHOP 表达减少。有趣的是，来自吸烟暴露小鼠的炎症细胞中 CHOP/ATF4 表达显著增加。
在体外急性香烟烟雾暴露后，多种人肺细胞类型中 CHOP 水平呈趋势增加。在体内，炎症细胞，主要是巨噬细胞，表现出明显的香烟烟雾诱导的 ER 应激。CHOP 在香烟烟雾中的早期诱导可能在肺部疾病的早期诱导中起关键作用，然而体内长期香烟烟雾暴露表现出 ER 应激反应的减少。
