title: Cigarette smoke-induced Egr-1 upregulates proinflammatory cytokines in pulmonary epithelial cells.
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.
authors.affiliation: Department of Internal Medicine, Pulmonary Division, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reynolds
authors.forename: Manuel G
authors.initials: MG
authors.lastname: Cosio
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D016373:DNA, Antisense / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D008168:Lung / Q000276:immunology*; D051379:Mice; D011656:Pulmonary Emphysema / Q000235:genetics / Q000276:immunology*; D012907:Smoking / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D016373:DNA, Antisense; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1