Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) embody multiple pathological features in common, such as chronic airway inflammation.The dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR) is causal to CF; however, its relationship to COPD has not been defined.In this study, we determined the role and signaling of CFTR in modulating cigarette smoke (CS)-induced COPD development.We found that the expression and function of CFTR was decreased in COPD mouse lung.Inhibition of CFTR by its inhibitor inh-172 potentiated mouse lung inflammation and lung function decline induced by CS.Exposure to cigarette smoke extract (CSE) led to reduced expression of CFTR, increased releases of IL-6 and-8, and greater activation of ERK1/2 and Nrf-2 in 16HBE airway epithelial cells.The CSE-induced changes of IL-6,-8, ERK1/2 and Nrf-2 were reinforced by inh-172 pretreatment.Inhibition of ERK1/2 attenuated CSE-indueed Nrf-2 activation.Knockdown of Nrf-2 by siRNA inhibited, whereas activation of Nrf-2 enhanced CSE-induced IL-6 and-8 releases by 16HBE cells.