Selective phosphodiesterase inhibitors modulate the activity of alveolar macrophages from sensitized guinea-pigs

The aim of this study was to investigate the effects of selective phosphodi esterase (PDE)3 and PDE4 inhibitors on arachidonate release by alveolar mac rophages from sensitized and challenged guinea-pigs, Guinea-pigs were sensitized and challenged with ovalbumin administered by a erosol, Bronchoalveolar lavage was performed 48 h later and the PDE and cyc lic adenosine monophosphate (cAMP) contents of or the arachidonate release from alveolar macrophages, stimulated in vitro with N-formyl-Met-Leu-Phe (f MLP), were evaluated, PDE3 and PDE4 activities were detected in preparations of macrophage lysate from sensitized challenged and sensitized control animals. Oral pretreatme nt, prior to antigen challenge in sensitized guinea-pigs, with rolipram or Ro 20-1724 (PDE4 inhibitors) but not milrinone (PDE3 inhibitor) significant ly reduced the arachidonate release from alveolar macrophages. In vitro inc ubation of alveolar macrophages from challenged guinea-pigs with Ro 20-1724 or the cAMP analogue dibutyryl cAMP (db-cAMP) but not milrinone or the cyc lic guanosine monophosphate (cGMP) analogue 8-bromo-cGMP (8-br-cGMP) signif icantly reduced arachidonate release, Incubation of the cells with a combin ation of milrinone plus rolipram or Ro 20-1724 elicited a marked and signif icant reduction in arachidonate release by alveolar macrophages stimulated with fMLP, In conclusion, these data show that phosphodiesterase-4 isoenzyme may regul ate the release of inflammatory mediators such as arachidonate from macroph ages through an increase in intracellular cyclic adenosine monophosphate, T his suggests that phosphodiesterase-4 inhibitors have potential in the trea tment of inflammatory disorders of the lung.