Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process
Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process
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DOI：
10.2147/copd.s19599
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发表时间：
2011-01-01
影响因子：
2.8
通讯作者：
D'Armiento, Jeanine M.
中科院分区：
文献类型：
--
作者：
Geraghty, Patrick;Wallace, Alison;D'Armiento, Jeanine M.
目的：吸烟是慢性阻塞性肺疾病（COPD）的主要危险因素。最近的研究提出了内质网（ER）应激和肺气肿之间的联系，在吸烟条件下增加的ER应激标志物证明。在这里，我们调查是否香烟烟雾诱导的内质网应激是细胞特异性的，并与急性和慢性香烟烟雾exposed.Methods：基因和蛋白质表达的变化，在人原代肺细胞培养后，香烟烟雾提取物（CSE）暴露的qPCR和蛋白质印迹分析进行了监测。将小鼠和豚鼠暴露于香烟烟雾中，并在全肺匀浆中检查ER应激标志物。10天烟雾暴露小鼠支气管肺泡灌洗液中的炎症细胞也examined.Results：香烟烟雾诱导的ER应激反应的趋势增加，通过激活转录因子4（ATF 4）介导的诱导C/EBP同源蛋白（CHOP）在原代小气道上皮细胞。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水平升高，但未达到显著水平。然而，在长期慢性香烟烟雾暴露后，CHOP表达减少。有趣的是，从烟雾暴露小鼠的炎症细胞有一个显着增加CHOP/ATF 4 expression.Conclusion：在CHOP水平的趋势增加出现在多种人肺细胞类型急性香烟烟雾暴露在体外。在体内，炎症细胞，主要是巨噬细胞，表现出显着的香烟烟雾诱导的ER应激。香烟烟雾中CHOP的早期诱导可能在肺部疾病的早期诱导中起关键作用，然而在体内长期香烟烟雾暴露显示ER应激反应减少。
Purpose: 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.Methods: 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.Results: 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.Conclusion: 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.