Role of cyclic adenosine monophosphate in reducing superoxide anion generation in guinea pig alveolar macrophages.
Aveolar macrophages (AM) may contribute to airway inflammation via release of superoxide anion (O2-). Elevation of intracellular cyclic adenosine monophosphate (cAMP) levels has been shown to suppress O2- generation, although the exact mechanism is uncertain. To examine the inhibitory effect of cAMP against different stimuli for O2- generation, we compared the effect of cAMP on O2- generation caused by phorbol myristate acetate (PMA), a direct protein kinase C activator, and N-formyl-methionyl-leucyl-phenylalanine (FMLP), which couples its membrane receptor and stimulates guanosine triphosphate binding protein, in guinea pig AM. Cyclic nucleotide phosphodiesterase (PDE) isoenzyme inhibitors or CPT-cAMP, a cAMP analogue, were used in order to increase intracellular cAMP levels. The O2- 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 O2- generation was not different between PMA and FMLP. Furthermore, CPT-cAMP also reduced PMA- or FMLP-induced O2- generation to a similar degree, although only high concentrations (10(-5) or 10(-4) mol/l) of this agent were effective in producing significant inhibition. A remarkable elevation of the cAMP level is required to produce the inhibitory effect on O2- generation in guinea pig AM. An elevation of cAMP may suppress O2- generation by inhibiting plural sites of the intracellular signaling pathways.
Department of Pediatrics, Gunma University School of Medicine, Maebashi, Japan.
K
K
Takei
K
K
Tokuyama
M
M
Kato
A
A
Morikawa
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D000077407:Cilostazol; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D006168:Guinea Pigs; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
D002273:Carcinogens; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D013777:Tetrazoles; D013873:Thionucleotides; D013481:Superoxides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D000077407:Cilostazol; D013755:Tetradecanoylphorbol Acetate