Anti-inflammatory effects of theophylline and selective phosphodiesterase inhibitors

Abstract

Theophylline has been used in the treatment of airway diseases, for more than 50 years with benefit thought to be derived from its ability to elicit bronchodilatation. Recent evidence has, however, suggested that theophylline possesses anti-inflammatory activity. The molecular mechanism of action remains unclear, although inhibition of the phosphodiesterase (PDE) enzyme, an enzyme which catalyzes the breakdown of cAMP and cGMP, has been proposed. Theophylline is a relatively weak inhibitor of PDE although there is evidence to suggest that PDE activity is elevated in leukocytes from patients with atopic disease. Thus, an altered responsiveness to PDE inhibitors may partly explain the mechanism of action of theophylline. The PDE enzyme exists as the least of seven different isoenzyme forms which can be characterized on the basis of a number of criteria including substrate specificity, sensitivity to selective inhibitors and the effect of allosteric modulators. The type IV isoenzyme is the predominant isoenzyme in inflammatory cells although it exists together with the type III isoenzyme in T-lymphocytes. There is considerable evidence from in vitro and in vivo studies suggesting that selective PDE IV inhibitors have antiinflammatory activity. The following article reviews these studies, together with clinical studies demonstrating that theophylline has anti-inflammatory activity.