Am. J. Respir. Cell Mol. Biol., Volume 20, Number 2, February, 1999 292-302

Identification and Function of Cyclic Nucleotide Phosphodiesterase Isoenzymes in Airway Epithelial Cells

Martin Fuhrmann, Hans-Ulrich Jahn, Joachim Seybold, Claus Neurohr, Peter J. Barnes, Stefan Hippenstiel, Hans Joachim Kraemer, and Norbert Suttorp

Department of Internal Medicine, Justus Liebig University of Giessen, Giessen, Germany; and Department of Thoracic Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom

Epithelial cells actively participate in inflammatory airway disease by liberating mediators such as arachidonate metabolites and cytokines. Inhibition of phosphodiesterases (PDEs) may be a useful anti-inflammatory approach. The PDE isoenzyme pattern and the effects of PDE inhibition on mediator generation were analyzed in primary cultures of human and porcine airway epithelial cells (AEC) and in the bronchial epithelial cell line BEAS-2B. PDE4 and PDE5 were detected in lysates of all cell types studied. In primary cultures of human AEC, the PDE4 variants PDE4A5, PDE4C1, PDE4D2, and PDE4D3 were identified by polymerase chain reaction analysis. Evidence of the recently described PDE7 was obtained by rolipram- insensitive cyclic adenosine monophosphate (cAMP) degradation, and its presence was verified by the demonstration of PDE7 messenger RNA. Primary cultures of human airway epithelium also expressed PDE1. Enhanced epithelial cAMP levels, induced by forskolin and PDE4 inhibition, increased formation of prostaglandin E₂ (PGE₂), but not of interleukin (IL)-8 or 15-hydroxyeicosatetraenoic acid (15-HETE) in airway epithelial cells. Increased cyclic guanosine monophosphate levels in these cells provoked by sodium nitroprusside and the PDE5 inhibitor zaprinast reduced the PGE₂ synthesis, whereas 15-HETE and IL-8 formation were unchanged. The data suggest that PDE isoenzymes are important in airway inflammation and that PDE inhibitors exert anti-inflammatory effects by acting on AEC.

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