The diseases of
cystic fibrosis,
chronic obstructive pulmonary disease (
COPD), and
chronic bronchitis are characterized by mucus-congested and inflamed airways.
Anti-inflammatory agents that can simultaneously restore or enhance mucociliary clearance through
cystic fibrosis transmembrane conductance regulator (CFTR) activation may represent new
therapeutics in their treatment. Herein, we report the activation of CFTR-mediated
chloride secretion by
phosphodiesterase (
PDE) 4 inhibitors in T84 monolayer using (125)I
anion as tracer. In the absence of
forskolin, the
iodide secretion was insensitive to
PDE4 inhibitor L-826,141 [4-[2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-ethyl]-3-methylpyridine-1-
oxide],
roflumilast, or to
PDE3 inhibitor trequinsin. However, these inhibitors potently augmented
iodide secretion after
forskolin stimulation, with efficacy coupled to the activation states of
adenylyl cyclase. The
iodide secretion from PDE3 or PDE4 inhibition was characterized at first by a prolonged efflux duration, followed by progressively elevated peak efflux rates at higher inhibitor concentrations. Paralleled with an increased phosphor-
cAMP response element-binding protein formation, the CFTR activation dissociated from a global cAMP elevation and was blocked by
H89 [N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide]. 2-(4-Fluorophenoxy)-N-[(1S)-1-(4-methoxyphenyl)ethyl]
nicotinamide, a stereoselective PDE4D inhibitor, augmented
iodide efflux more efficiently than its less potent (R)-isomer. The peak efflux from maximal PDE4 and PDE3 inhibition matched that from full
adenylyl cyclase activation. These data suggest that PDE3 and PDE4 (mainly PDE4D) form the major cAMP diffusion barrier in T84 cells to ensure a compartmentalized CFTR signaling. Together with their potent anti-inflammatory properties, the potentially enhanced airway mucociliary clearance from CFTR activation may have contributed to the efficacy of
PDE4 inhibitors in
COPD and asthmatic patients.
PDE4 inhibitors may represent new opportunities to combat
cystic fibrosis and other
respiratory diseases in future.