Chronic obstructive pulmonary disease (COPD) is a growing cause of morbidity and mortality worldwide and is the third leading cause of death in the United States. Roflumilast is a cAMP-specific PDE4 inhibitor that has been shown to improve lung function and reduce exacerbations in COPD and is approved for the treatment of exacerbations in severe COPD1. Roflumilast has also been shown to activate CFTR in epithelial cells2. Chronic smokers lack CFTR activity in vivo and have dehydrated mucus3. Airway surface liquid (ASL) volume regulation is vital for mucus clearance within the lungs and in cigarette smoke (CS)-exposed airways this system fails due to the removal of CFTR from the apical plasma membrane. Thus we tested the hypothesis that Roflumilast could prevent CS-induced ASL volume depletion in HBECs by hyperactivating CFTR that remains in the membrane post-CS exposure. RESULTS: Roflumilast significantly increased cAMP levels in HBEC cells exposed to ADO (p<0.05). To determine whether Roflumilast would be effective in airway epithelia after cigarette smoke exposure, we measured cAMP levels in air or CS-exposed HBECs. Surprisingly, Roflumilast significantly potentiated the ADO-induced cAMP increase in cigarette smoke in cultures as compared to air controls that were also exposed to Roflumilast (p<0.05). This effect was mirrored by the increase in ASL height seen with Roflumilast following cigarette smoke exposure. With Roflumilast pre-treatment, ADO raised ASL height into the normal range after CS exposure. Roflumilast treatment after CS exposure also aids ASL recovery compared to controls and returns ASL to within the normal range (~7 um) (p<0.05), whereas Isoproteranol (short acting beta agonist) and Salmeterol (long acting beta agonists) do not appear to have an effect on ASL height after CS exposure. The effect of Roflumilast on cilliary beat frequency (CBF) before and after CS exposure is currently being studied. CONCLUSIONS: In addition to triggering removal of CFTR from the plasma membrane, CS likely also alters cAMP metabolism, as revealed by Roflumilast pre-treatment. Our data suggest that the potentiation of the ADO/cAMP response with Roflumilast brings ASL height into the normal range during CS exposure and may help rehydrate the airways of COPD patients. Preliminary results indicate that Roflumilast may also be more effective than short acting beta-agonists at preventing mucus dehydration seen in COPD.