Abstract
Background: COPD is a devastating disease characterized by chronic bronchitis and emphysema. The Wnt/β-catenin signaling has been implicated in emphysema, but its role in the pathogenesis of chronic bronchitis remains unknown.
Methods: Human lung tissues were obtained from 4 groups of patients: healthy nosmokers (n=7), healthy smokers (n=7), COPD nosmokers (n=10) and COPD smokers (n=18). Human airway epithelial cells (16HBE) were treated with cigarette smoke extract (CSE; 0, 2%, 4% or 8%) for 24h. Mice were treated with cigarette smoke (CS) exposure (200mg TPM/m3, 4h/d, 5d/wk) and SB-216763 injection (a GSK3β inhibitor, 3mg/kg/d, i.p.) for 1 month. The activation of Wnt /β-catenin signaling was analyzed by RT-PCR and western blot.
Results: We observed a significant increase in mRNA levels of Wnt antagonist Wif-1 (10.5-fold) and a decrease in Wnt receptor Fzd4 expression in COPD smokers as compared to COPD nonsmokers. Expression of β-catenin/Tcf4 was also reduced in COPD smokers compared with healthy smokers, indicating impaired Wnt activity in smoking-related COPD. In 16HBE cells, CSE induced the expression of Wnt antagonists Wif-1 and Dkk1, while reduced β-catenin and Tcf4/Lef1 expression. In vivo, the mRNA levels of Wnt antagonists Wif-1 and Sfrp1 were elevated 2.5-fold and 1.6-fold respectively in CS-exposed mice. SB-216763 treatment attenuated CS–induced BALF total leukocyte and macrophage accumulation, airway inflammation and β-catenin downregulation.
Conclusion: Decreased Wnt/β-catenin signaling may be involved in airway inflammation and airway epithelium injury. Overexpression of Wnt antagonists may contribute to this process, implicating potential therapeutic targets for the treatment of COPD.
- © 2012 ERS