Modulation of eotaxin formation and eosinophil migration by selective inhibitors of phosphodiesterase type 4 isoenzyme

1 This study was undertaken to investigate the possible contribution of the blockade of eotaxin generation to the anti-eosinophilotactic effect of pho sphodiesterase (PDE) type 4 inhibitors. In some experiments, the putative s ynergistic interaction between PDE type 4 inhibitors and the beta2-agonist salbutamol was also assessed. 2 Sensitized guinea-pigs aerosolized with antigen (5% ovalbumin, OVA) respo nded with a significant increase in eotaxin and eosinophil levels in the br onchoalveolar lavage fluid (BALF) at 6 h. Eosinophil recruitment was inhibi ted by both PDE type 4 inhibitors rolipram (5 mg kg(-1), i.p.) and RP 73401 (5 mg kg(-1), i.p.) treatments. In contrast, only rolipram inhibited eotax in production. 3 Sensitized rats intrapleurally challenged (i.pl.) with antigen (OVA, 12 m ug cavity(-1)) showed a marked eosinophil infiltration at 24 h, preceded by eotaxin generation at 6 h. Intravenous administration of a rabbit anti-mou se eotaxin antibody (0.5 mg kg(-1)) significantly reduced allergen-evoked e osinophilia in this model. 4 Local pretreatment with rolipram (40 mug cavity(-1)) or RP 73401 (40 mug cavity(-1)) 1 h before challenge reduced eosinophil accumulation evaluated in the rat pleural effluent, but only the former was active against eotaxin generation. The inhibitors of PDE type 3 (SK&F 94836) and type 5 (zaprinas t) failed to alter allergen-evoked eosinophil recruitment in rats. 5 Local injection of beta2-agonist salbutamol (20 mug cavity(-1)) inhibited both eosinophil accumulation and eotaxin production following pleurisy. Th e former was better inhibited when salbutamol and rolipram were administere d in combination. 6 Treatment with rolipram and RP 73401 dose-dependently inhibited eosinophi l adhesion and migration in vitro. These effects were clearly potentiated b y salbutamol at concentrations that had no effect alone. 7 Our findings indicate that although rolipram and RP 73401 are equally eff ective in inhibiting allergen-induced eosinophil infiltration only the form er prevents eotaxin formation, indicating that PDE 4 inhibitors impair eosi nophil accumulation by mechanisms independent of eotaxin production blockad e.