EFFECTS OF AGENTS WHICH ELEVATE CYCLIC-AMP ON GUINEA-PIG EOSINOPHIL HOMOTYPIC AGGREGATION

1 Eosinophil recruitment and activation in inflamed tissue is thought to play an important role in the pathophysiology of allergic diseases. Experimental evidence suggests that elevating cyclic AMP is an effect ive means of reducing eosinophil recruitment in vivo and may therefore have therapeutic benefit. In the present study, we have assessed the capacity of cyclic AMP-elevating agents to modulate guinea-pig eosinop hil homotypic aggregation, a CD18-dependent process, which may be an i mportant component of eosinophil function in vivo. 2 Prostaglandin E(1 ) (PGE(1), 10(-10) to 10(-6) M) inhibited platelet activating-factor ( PAF)- and C5a-induced eosinophil aggregation in a concentration-depend ent manner. However, PAF-induced responses were more potently and more effectively inhibited by PGE(1). The inhibitory effects of PGE, on PA F-induced aggregation were reversed by pretreatment of eosinophils wit h the protein kinase A inhibitors H89 and KT5720. 3 The beta(2)-adreno ceptor agonists, salbutamol and salmeterol, concentration-dependently inhibited eosinophil aggregation induced by C5a and PAF and, again, PA F-induced responses were more effectively reduced. The inhibitory effe ct of salmeterol was mediated by beta-adrenoceptors, as assessed by th e reversal after pretreatment with propranolol. 4 Rolipram, a selectiv e phosphodiesterase 4 (PDE4) inhibitor, also attenuated PAF- and C5a-i nduced aggregation and at a low concentration which did not affect agg regation per se, had a synergistic effect with PGE(1) and salbutamol t o suppress this response. 5 Activation of eosinophils with PAF or C5a induced a small but significant increase in the level of CD18 expressi on on the eosinophil surface. PGE(1) (10(-7) M) decreased PAF- and C5a -induced upregulation of CD18 by 93% and 62%, respectively. 6 These re sults demonstrate that cyclic AMP-elevating agents effectively inhibit eosinophil aggregation, a CD18-dependent functional response. Because CD18 has been shown to be important for eosinophil recruitment to inf lamed tissue in vivo, our findings may be of relevance to the efficacy of cyclic AMP-elevating agents at inhibiting eosinophil trafficking.