PHOSPHODIESTERASE-IV INHIBITORS AS THERAPY FOR EOSINOPHIL-INDUCED LUNG INJURY IN ASTHMA

Asthma is a complex, multifactorial disease that is underpinned by airway inflammation. A variety of cytotoxic substances are released into the airway from infiltrating inflammatory cells, especially the eosinophil. These cytotoxic substances, including reactive oxygen metabolites, produce damage to the airway epithelium, a histologic feature of chronic asthma. Damage to the airway epithelium, in turn, is thought to be a major factor responsible for the development of airway hyperreactivity, a hallmark of asthma. One notable molecular target for novel antiasthmatic drugs is the cyclic AMP-specific phosphodiesterase (PDE) or PDE IV. This isozyme is the predominant form of cyclic nucleotide PDE activity in inflammatory cells. Thus, in view of the putative role of cyclic AMP as an inhibitory second messenger in these cells, PDE IV inhibitors have been shown to suppress inflammatory cell activity. The purpose of the present experiments was to examine the effect of the PDE IV inhibitor, R-rolipram, on three key functions of the guinea pig eosinophil: a) superoxide anion (O-2(-)) production, b) adhesion to human umbilical vein endothelial cells (HUVECs), and c) infiltration into the airway. R-rolipram-elevated eosinophil cyclic AMP content (EC(50)=1.7 mu M) and inhibited fMLP-induced O-2(-) production in a concentration-dependent manner (IC50=0.3 mu M). In contrast, neither siguazodan, a PDE III inhibitor, nor zaprinast, a PDE V inhibitor, had an appreciable effect. R-rolipram (30 mu M) also reduced by 25 to 40% the adhesion of eosinophils to HUVECs stimulated with phorbol myristate acetate or tumor necrosis factor-alpha, particularly under conditions in which both cell types were simultaneously exposed to the PDE IV inhibitor. Again, siguazodan and zaprinast had little or no effect. Finally, pretreatment of conscious guinea pigs with R-rolipram (1-10 mg/kg, intragastric) produced a dose-dependent inhibition of antigen-induced eosinophil infiltration into the airway. Thus, by virtue of their ability to modify eosinophil function at several levels, PDE IV inhibitors may reduce epithelial cell damage associated with asthma.