Cyclic nucleotides and phosphodiesterases and airway function.

The cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play an important role in the regulation of airway smooth muscle tone and activation of inflammatory cells. Intracellular concentrations of these nucleotides are tightly regulated by phosphodiesterases (PDEs). Several families of PDEs are now recognized and, within each isoenzyme family, molecular cloning has revealed multiple members. PDE III and IV are important in the breakdown of cAMP; PDE III is involved in the regulation of airway smooth muscle tone, whereas PDE IV is more important in inflammatory cells, including mast cells, macrophages, eosinophils, T-lymphocytes and epithelial cells. PDE V is involved in the breakdown of cGMP in airway and vascular smooth muscle. Regulation of PDE expression in health and disease is now under investigation. Several selective PDE inhibitors have recently been developed, and experimental studies indicate that PDE IV inhibitors may be useful as anti-inflammatory treatments in asthma. Clinical trials in asthma are now in progress.