Identification and function of cyclic nucleotide phosphodiesterase isoenzymes in airway epithelial cells

Epithelial cells actively participate in inflammatory airway disease by lib erating mediators such as arachidonate metabolites and cytokines. Inhibitio n of phosphodiesterases (PDEs) may be a useful anti-inflammatory approach. The PDE isoenzyme pattern and the effects of PDE inhibition on mediator gen eration were analyzed in primary cultures of human and porcine airway epith elial cells (AEC) and in the bronchial epithelial cell line BEAS-2B. PDE4 a nd PDES were detected in lysates of all cell types studied. In primary cult ures of human AEC, the PDE4 variants PDE4A5, PDE4C1, PDE4D2, and PDE4D3 wer e identified by polymerase chain reaction analysis. Evidence of the recentl y described PDE7 was obtained by rolipram-insensitive cyclic adenosine mono phosphate (cAMP) degradation, and its presence was verified by the demonstr ation of PDE7 messenger RNA. Primary cultures of human airway epithelium al so expressed PDE1. Enhanced epithelial cAMP levels, induced by forskolin an d PDE4 inhibition, increased formation of prostaglandin E-2 (PGE(2)), but n ot of interleukin (IL)-8 or 15-hydroxyeicosatetraenoic acid (15-HETE) in ai rway epithelial cells. Increased cyclic guanosine monophosphate levels in t hese cells provoked by sodium nitroprusside and the PDES inhibitor zaprinas t reduced the PGE(2) synthesis, whereas 15-HETE and IL-8 formation were unc hanged. The data suggest that PDE isoenzymes are important in airway inflam mation and that PDE inhibitors exert anti-inflammatory effects by acting on AEC.