Modifier Role of Nrf2 in Cigarette Smoke–induced Emphysema

Background: CCAAT/enhancer binding proteins (C/EBPs) are key regulators of cell differentiation and linked processes such as proliferation, apoptosis, and gene expression in several organs. C/EBPs are also central for inflammatory responses and infectious defenses, but so far little is known of their role in lung diseases. Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are common smoking-associated lung diseases involving the airway epithelium. Methods: Gel shifts were used to study C/EBP transcription factor activity in airway epithelial cells obtained by bronchial brush biopsy in four groups: healthy never-smokers (n 10), asymptomatic smokers (n 7), and smokers with chronic bronchitis and recurrent infectious exacerbations without (n 23) and with (n 13) COPD. Results: C/EBP-binding activity was increased 4.6-fold in airway epithelial cells of healthy smokers compared with never-smokers. In contrast, C/EBP-binding activity was not increased in the epithelium of smokers with chronic bronchitis or COPD. C/EBP was the dominant C/EBP in the airway epithelium in all groups. Conclusions: We hypothesize that this lack of increase in C/EBP-activity renders the epithelium incompetent of efficient regeneration and more sensitive to infection, suggesting a previously unknown role for C/EBPs in the pathogenesis of chronic bronchitis and COPD. In addition, decreased C/EBP-activity in chronic bronchitis and COPD could contribute to the glucocorticoid resistance of these diseases.