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Published ahead of print on April 6, 2006, doi:10.1165/rcmb.2005-0428OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 3, September 2006, 314-319

A more recent version of this article appeared on September 1, 2006
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Submitted on November 18, 2005
Revised on April 5, 2006

Cigarette Smoke-induced Egr-1 Upregulates Pro-inflammatory Cytokines in Pulmonary Epithelial Cells

Paul R Reynolds1, Manuel C Cosio2, and John R Hoidal1*

1 Department of Internal Medicine, Pulmonary Division, University of Utah Health Sciences Center, Salt Lake City, UT, USA, 2 Meakins-Christie Laboratories, Respiratory Division, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada

* To whom correspondence should be addressed. E-mail: john.hoidal{at}hsc.utah.edu.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is a progressive and irreversible disorder. Cigarette smoke 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, 2004). 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 endogenous Egr-1 markedly induce Egr-1 expression following CSE exposure. In order to evaluate Egr-1-specific effects, we utilized antisense ({alpha}S) oligodeoxynucleotides (ODN) to knock down Egr-1 expression. Incorporation of Egr-1 {alpha}S ODN significantly decreased CSE-induced Egr-1 mRNA and protein, while sense ODN had no effect. Via Egr-1-mediated mechanisms, IL-1{beta} 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 pro-inflammatory mechanisms that likely contribute to the development of COPD in the lungs of smokers.




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