The development of potent modulators of cystic fibrosis transmembrane regulator (CFTR) activity has raised the possibility that pharmacologic enhancement of CFTR function may have important clinical significance, even among individuals without congenital mutations in the CF gene. New pharmacologic agents capable of robustly stimulating chloride secretion through CFTR point to novel treatment strategies for common diseases of mucus stasis, including chronic obstructive pulmonary disease (COPD) caused by tobacco exposure. Preliminary data presented in this application establish that patients with COPD and tobacco exposure exhibit reduced CFTR activity in vivo and in vitro and that acquired CFTR dysfunction may contribute to COPD pathogenesis. Recent results from our laboratory have also shown that potentiation of CFTR with the molecule VX-770, an agent shown to rescue the basic defect in CF patients with the G551D-CFTR gating mutation, can restore CFTR function following cigarette smoke exposure, suggesting a potential new therapeutic strategy for individuals with COPD. In these studies, we will investigate the hypothesis that tobacco smoke exposure induces mucus stasis due to an acquired state of CFTR dysfunction in some individuals with COPD, and this state can be reversed by application of a potentiator of CFTR channel gating. In Aim 1, we will define the prevalence and severity of CFTR deficiency in the lower airway by determining intrabronchial CFTR activity and expression in the setting of COPD. Studies will include COPD patients who do and do not actively smoke, healthy smokers, and normal controls, and will establish the COPD sub-phenotype associated with acquired CFTR dysfunction In Aim 2, we will determine the cellular mechanisms underlying acquired CFTR dysfunction by tobacco smoke exposure using cell culture models and tissues highly predictive of in vivo results, and test whether CFTR dysfunction can be reversed by administration of VX-770, a potentiator of CFTR gating. In Aim 3, we will investigate downstream effects of tobacco exposure and CFTR modulation on airway surface liquid regulation, mucus transport, and mucus rheology using novel methods we have developed to characterize basic properties of pulmonary epithelia. Results will define COPD clinical characteristics attributable to relative CFTR dysfunction, the mechanisms that underlie this phenomenon, and the propensity of CFTR potentiators to reverse this defect. Completion of the proposal will establish a novel COPD sub-phenotype and set the stage for a new treatment paradigm in COPD. PUBLIC HEALTH RELEVANCE: The advent of potentiators of CFTR activity raises the possibility that pharmacologic enhancement of dysfunctional CFTR may ameliorate diseases in individuals with acquired forms of CFTR dysfunction, even in individuals without mutations in the CF gene. An understanding of the mechanism and severity of lower airway CFTR dysfunction in COPD will lead to new insights into disease pathogenesis and establish CFTR as a therapeutic target in the disease. Completion of this proposal with define a novel COPD sub-phenotype characterized by CFTR dysfunction, and set the stage for further studies to explore the role of CFTR modulation in patients with COPD.