Reynolds Paul R, Cosio Manuel G, Hoidal John R
Department of Internal Medicine, Pulmonary Division, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
Am J Respir Cell Mol Biol. 2006 Sep;35(3):314-9. doi: 10.1165/rcmb.2005-0428OC. Epub 2006 Apr 6.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is a progressive and irreversible disorder. Cigarette smoking is associated with 80-90% of COPD cases; however, the genes involved in COPD-associated emphysema and chronic inflammation are poorly understood. It was recently demonstrated that early growth response gene 1 (Egr-1) is significantly upregulated in the lungs of smokers with COPD (Ning W and coworkers, Proc Natl Acad Sci 2004;101:14895-14900). We hypothesized that Egr-1 is activated in pulmonary epithelial cells during exposure to cigarette smoke extract (CSE). Using immunohistochemistry, we demonstrated that pulmonary adenocarcinoma cells (A-549) and primary epithelial cells lacking basal Egr-1 markedly induce Egr-1 expression after CSE exposure. To evaluate Egr-1-specific effects, we used antisense (alphaS) oligodeoxynucleotides (ODN) to knock down Egr-1 expression. Incorporation of Egr-1 alphaS ODN significantly decreased CSE-induced Egr-1 mRNA and protein, while sense ODN had no effect. Via Egr-1-mediated mechanisms, IL-1beta and TNF-alpha were significantly upregulated in pulmonary epithelial cells exposed to CSE or transfected with Egr-1. To investigate the relationship between Egr-1 induction by smoking and susceptibility to emphysema, we determined Egr-1 expression in strains of mice with different susceptibilities for the development of smoking-induced emphysema. Egr-1 was markedly increased in the lungs of emphysema-susceptible AKR/J mice chronically exposed to cigarette smoke, but only minimally increased in resistant NZWLac/J mice. In conclusion, Egr-1 is induced by cigarette smoke and functions in proinflammatory mechanisms that likely contribute to the development of COPD in the lungs of smokers.
慢性阻塞性肺疾病（COPD）是全球第四大致死原因，是一种进行性且不可逆的疾病。80 - 90%的COPD病例与吸烟有关；然而，与COPD相关的肺气肿和慢性炎症所涉及的基因仍知之甚少。最近有研究表明，早期生长反应基因1（Egr - 1）在患有COPD的吸烟者肺中显著上调（宁W及其同事，《美国国家科学院院刊》2004年；101:14895 - 14900）。我们推测，在暴露于香烟烟雾提取物（CSE）期间，Egr - 1在肺上皮细胞中被激活。通过免疫组织化学，我们证明肺腺癌细胞（A - 549）和缺乏基础Egr - 1的原代上皮细胞在暴露于CSE后显著诱导Egr - 1表达。为了评估Egr - 1的特异性作用，我们使用反义（αS）寡脱氧核苷酸（ODN）来敲低Egr - 1表达。掺入Egr - 1αS ODN显著降低了CSE诱导的Egr - 1 mRNA和蛋白质水平，而正义ODN则无此作用。通过Egr - 1介导的机制，暴露于CSE或转染Egr - 1的肺上皮细胞中白细胞介素 - 1β（IL - 1β）和肿瘤坏死因子 - α（TNF - α）显著上调。为了研究吸烟诱导的Egr - 1与肺气肿易感性之间的关系，我们测定了对吸烟诱导的肺气肿具有不同易感性的小鼠品系中的Egr - 1表达。长期暴露于香烟烟雾的肺气肿易感AKR/J小鼠肺中Egr - 1明显增加，但抗性NZWLac/J小鼠中仅轻微增加。总之，香烟烟雾可诱导Egr - 1，其在促炎机制中发挥作用，这可能促使吸烟者肺部发生COPD。
