ROLE OF CYCLIC ADENOSINE-MONOPHOSPHATE IN REDUCING SUPEROXIDE ANION GENERATION IN GUINEA-PIG ALVEOLAR MACROPHAGES

Alveolar macrophages (AM) may contribute to airway inflammation via re lease of superoxide anion (O-2(-)). Elevation of intracellular cyclic adenosine monophosphate (cAMP) levels has been shown to suppress O-2(- ) generation, although the exact mechanism is uncertain. To examine th e inhibitory effect of cAMP against different stimuli for O-2(-) gener ation, we compared the effect of cAMP on O-2(-) generation caused by p horbol myristate acetate (PMA), a direct protein kinase C activator, a nd N-formyl-methionyl-leucyl-phenylalanine (FMLP), which couples its m embrane receptor and stimulates guanosine triphosphate binding protein , in guinea pig AM. Cyclic nucleotide phosphodiesterase (PDE) isoenzym e inhibitors or CPT-cAMP, a cAMP analogue, were used in order to incre ase intracellular cAMP levels. The O-2(-) generation caused by either PMA or FMLP was reduced by cilostazol (PDE 3 inhibitor) and Ro20-1724 (PDE 4 inhibitor), but not by zaprinast (PDE 5 inhibitor). The degree of reduction in O-2(-) generation was not different between PMA and FM LP. Furthermore, CPT-cAMP also reduced PMA- or FMLP-induced O-2(-) gen eration to a similar degree, although only high concentrations (10(-5) or 10(-4) mol/l) of this agent were effective in producing significan t inhibition. A remarkable elevation of the cAMP level is required to produce the inhibitory effect on O-2(-) generation in guinea pig AM. A n elevation of cAMP may suppress O-2(-) generation by inhibiting plura l sites of the intracellular signaling pathways.