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 effective 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 eosinophil homotypic aggregation, a CD18-dependent process, which may be an important component of eosinophil function in vivo. 2. Prostaglandin E1 (PGE1, 10(-16) to 10(-6) M) inhibited platelet activating-factor (PAF)- and C5a-induced eosinophil aggregation in a concentration-dependent manner. However, PAF-induced responses were more potently and more effectively inhibited by PGE1. The inhibitory effects of PGE1 on PAF-induced aggregation were reversed by pretreatment of eosinophils with the protein kinase A inhibitors H89 and KT5720. 3. The beta 2-adrenoceptor agonists, salbutamol and salmeterol, concentration-dependently inhibited eosinophil aggregation induced by C5a and PAF and, again. PAF-induced responses were more effectively reduced. The inhibitory effect of salmeterol was mediated by beta-adrenoceptors, as assessed by the reversal after pretreatment with propranolol. 4. Rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, also attenuated PAF- and C5a-induced aggregation and at a low concentration which did not affect aggregation per se, had a synergistic effect with PGE1 and salbutamol to suppress this response. 5. Activation of eosinophils with PAF or C5a induced a small but significant increase in the level of CD18 expression on the eosinophil surface. PGE1 (10(-7) M) decreased PAF- and C5a-induced upregulation of CD18 by 93% and 62%, respectively. 6. These results 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 inflamed tissue in vivo, our findings may be of relevance to the efficacy of cyclic AMP-elevating agents at inhibiting eosinophil trafficking.
Teixeira
M M
MM
National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London.
Rossi
A G
AG
Giembycz
M A
MA
Hellewell
P G
PG
D000420:Albuterol / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects*; D005260:Female; D006168:Guinea Pigs; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011760:Pyrrolidinones; D000242:Cyclic AMP; D000527:Alprostadil; D020889:Rolipram; D015232:Dinoprostone; D000420:Albuterol