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Am J Respir Cell Mol Biol. 2006 Sep;35(3):314-9. Epub 2006 Apr 6.

Cigarette smoke-induced Egr-1 upregulates proinflammatory cytokines in pulmonary epithelial cells.

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1
Department of Internal Medicine, Pulmonary Division, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.

Abstract

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.

PMID:
16601242
PMCID:
PMC2643284
DOI:
10.1165/rcmb.2005-0428OC
[Indexed for MEDLINE]
Free PMC Article
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