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

Asthma is a complex, multifactorial disease that is underpinned by air way inflammation. A variety of cytotoxic substances are released into the airway from infiltrating inflammatory cells, especially the eosino phil. These cytotoxic substances, including reactive oxygen metabolite s, produce damage to the airway epithelium, a histologic feature of ch ronic asthma. Damage to the airway epithelium, in turn, is thought to be a major factor responsible for the development of airway hyperreact ivity, a hallmark of asthma. One notable molecular target for novel an tiasthmatic drugs is the cyclic AMP-specific phosphodiesterase (PDE) o r PDE IV. This isozyme is the predominant form of cyclic nucleotide PD E activity in inflammatory cells. Thus, in view of the putative role o f 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 P DE IV inhibitor, R-rolipram, on three key functions of the guinea pig eosinophil: a) superoxide anion (O-2(-)) production, b) adhesion to hu man umbilical vein endothelial cells (HUVECs), and c) infiltration int o the airway. R-rolipram-elevated eosinophil cyclic AMP content (EC(50 )=1.7 mu M) and inhibited fMLP-induced O-2(-) production in a concentr ation-dependent manner (IC50=0.3 mu M). In contrast, neither siguazoda n, a PDE III inhibitor, nor zaprinast, a PDE V inhibitor, had an appre ciable effect. R-rolipram (30 mu M) also reduced by 25 to 40% the adhe sion of eosinophils to HUVECs stimulated with phorbol myristate acetat e or tumor necrosis factor-alpha, particularly under conditions in whi ch both cell types were simultaneously exposed to the PDE IV inhibitor . Again, siguazodan and zaprinast had little or no effect. Finally, pr etreatment of conscious guinea pigs with R-rolipram (1-10 mg/kg, intra gastric) produced a dose-dependent inhibition of antigen-induced eosin ophil infiltration into the airway. Thus, by virtue of their ability t o modify eosinophil function at several levels, PDE IV inhibitors may reduce epithelial cell damage associated with asthma.