BACKGROUND: Phosphodiesterases (PDEs) break down @entity268 , thereby regulating intracellular @entity268 concentrations and diffusion. Since @entity1980 predominates in airway epithelial cells, @entity1980 inhibitors can stimulate @entity5174 ( @entity5174 ) by increasing @entity268 . @entity286 smoking and @entity1030 are associated with decreased @entity5174 function and impaired mucociliary clearance (MCC). However, the effects of the @entity1980 inhibitor @entity21041 on smoke-induced @entity409 have not been fully explored. METHODS: Primary normal @entity1 bronchial epithelial cells (NHBE) from non-smokers, cultured at the air-liquid interface (ALI) were used for most experiments. Cultures were exposed to cigarette smoke in a Vitrocell VC-10 smoking robot. To evaluate the effect of @entity21041 on intracellular @entity268 concentrations, fluorescence resonance energy transfer (FRET) between @entity9861 (PKA) subunits was recorded. Airway surface liquid (ASL) was measured using light refraction scanning and ciliary beat frequency (CBF) employing infrared differential interference contrast microscopy. @entity2865 conductance was measured in Ussing chambers and @entity5174 expression was quantified with qPCR. RESULTS: While treatment with 100 nM @entity21041 had little effect alone, it increased intracellular @entity268 upon stimulation with @entity1928 and @entity3045 in cultures exposed to cigarette smoke and in control conditions. @entity268 baselines were lower in smoke-exposed cells. @entity21041 prolonged @entity268 increases in smoke-exposed and control cultures. Smoke-induced reduction in functional, @entity3045 -mediated @entity2865 conductance through @entity5174 was improved by @entity21041 . ASL volumes also increased in smoke-exposed cultures in the presence of @entity21041 while it did not in its absence. Cigarette smoke exposure decreased CBF, an effect rescued with @entity21041 , particularly when used together with the long-acting   -mimetic @entity6410 . @entity21041 also enhanced @entity1928 -induced CBF stimulation in ASL volume supplemented smoked and control cells, confirming the direct stimulatory effect of rising @entity268 on ciliary function. In active smokers, @entity5174 mRNA expression was increased compared to non-smokers and ex-smokers. @entity21041 also increased @entity5174 mRNA levels in cigarette-smoke exposed cell cultures. CONCLUSIONS: Our results show that @entity21041 can rescue smoke-induced @entity409 by reversing decreased @entity5174 activity, augmenting ASL volume, and stimulating CBF, the latter particularly in combination with @entity6410 . As expected, @entity5174 mRNA expression was not indicative of apical @entity5174 function.

XXXX partially reverses smoke-induced @entity409 .

@entity268 :: ('CHEBI:17489', 'Chemical') :: ['cAMP'] @entity286 :: ('4097', 'Species') :: ['Tobacco'] @entity1 :: ('9606', 'Species') :: ['human'] @entity5174 :: ('1080', 'Gene') :: ['CFTR', 'Cystic Fibrosis Transmembrane Conductance Regulator'] @entity1980 :: ('5141', 'Gene') :: ['PDE4'] @entity2865 :: ('CHEBI:17996', 'Chemical') :: ['Chloride', 'chloride'] @entity3045 :: ('MESH:D000420', 'Chemical') :: ['albuterol'] @entity409 :: ('MESH:D008107', 'Disease') :: ['mucociliary dysfunction'] @entity21041 :: ('MESH:C424423', 'Chemical') :: ['Roflumilast', 'roflumilast'] @entity1030 :: ('MESH:D029424', 'Disease') :: ['COPD'] @entity9861 :: ('5199', 'Gene') :: ['CFP- and YFP-tagged protein kinase A'] @entity6410 :: ('MESH:C012629', 'Chemical') :: ['formoterol'] @entity1928 :: ('MESH:D005576', 'Chemical') :: ['forskolin']
@entity21041 :: (MESH:C424423,Chemical) :: ['Roflumilast']
