EFFECTS OF PHOSPHODIESTERASE ISOENZYME INHIBITORS ON CUTANEOUS INFLAMMATION IN THE GUINEA-PIG

1 Inflammation is central to the pathophysiology of asthma. The recent findings that different inflammatory cells may express different phos phodiesterase (PDE) isoenzymes have centred attention on inhibitors of these isoenzymes as new drugs for the treatment of asthma. In this st udy, we investigated the effect of different PDE isoenzyme inhibitors on the accumulation of In-111-labelled eosinophils and local oedema fo rmation at sites of allergic- and mediator-induced inflammation in gui nea-pig skin. 2 Systemic treatment with SK&F 94120, a type III PDE inh ibitor, or zaprinast, a type V PDE inhibitor, had no effect on the In- 111-eosinophil accumulation and oedema formation induced by i.d. injec tion of zymosan-activated plasma (ZAP), PAF, histamine or in a passive cutaneous anaphylaxis (PCA) reaction. 3 Systemic treatment with rolip ram, a type IV PDE inhibitor, effectively inhibited In-111-eosinophil accumulation induced by ZAP, PAF, histamine and in a PCA reaction. How ever, oedema formation measured in the same sites was not affected. Sy stemic administration of higher doses of theophylline produced similar results. In contrast, In-111-neutrophil accumulation induced by ZAP o r in a PCA reaction was not altered by systemic treatment with rolipra m. 4 Locally-injected rolipram had little effect on In-111-eosinophil accumulation and oedema formation induced by histamine, PAF and in a P CA reaction. 5 These data show that systemic, but not local, treatment with rolipram effectively inhibits allergic- and mediator-induced In- 111-eosinophil accumulation but not oedema formation or In-111-neutrop hil accumulation. This, taken together with the potent inhibitory effe cts of PDE type IV inhibitors on eosinophil function in vitro, suggest that this class of drugs may be beneficial in disease states such as asthma where eosinophils are thought to play a major pathophysiologica l role.