Inhibition of antigen-induced pulmonary eosinophilia and neutrophilia by selective inhibitors of phosphodiesterase types 3 or 4 in Brown Norway rats.
Rolipram, a phosphodiesterase type 4 (PDE4)-selective inhibitor, has been demonstrated to inhibit antigen-induced pulmonary eosinophilia in guinea pigs and monkeys, suggesting that PDE4-selective inhibitors could be useful for treating asthma. Although the rat is used extensively in preclinical drug development, a pulmonary antiinflammatory effect of PDE4 inhibition has not been demonstrated in this species. Therefore, we examined the effects of rolipram, CI-930 (PDE3-selective inhibitor), zaprinast (PDE5-selective inhibitor) and aminophylline on antigen-induced pulmonary inflammatory cell influx in Brown Norway rats. Two weeks after sensitization rats were exposed to aerosolized ovalbumin and 24 h later bronchoalveolar lavage (BAL) was performed for determinations of total cell counts and cell type differentials. The resulting 10-fold increase in total cell counts was due primarily to an increase in eosinophils (from 0.06 to 11.0 x 10(6)) and neutrophils (from 0.02 to 12 x 10(6)). Rolipram, CI-930 and aminophylline, given p.o. before and after antigen challenge, each completely inhibited eosinophil influx, with B.I.D. ED50 values of 0.5, 0.4 and 39 mg/kg, respectively. Rolipram, CI-930 and aminophylline each completely inhibited neutrophil influx as well, with B.I.D. ED50 values of 0.1, 0.5 and 20 mg/kg, respectively. Denbufylline and milrinone (10 mg/kg p.o.) also inhibited eosinophil and neutrophil influx, consistent with PDE4 and PDE3 inhibition as the mechanisms of action of rolipram and CI-930, respectively. In contrast, zaprinast was inactive at 0.3-30 mg/kg. However, the beta2 agonist salbutamol greatly inhibited antigen-induced pulmonary eosinophilia and neutrophilia, with p.o. B.I.D. ED50 values of 2.1 and 2.3 mg/kg, respectively, indicating that drugs which increase intracellular cAMP levels by one of several mechanisms can inhibit antigen-induced pulmonary inflammation in rats. In conclusion, these results demonstrate that PDE4 inhibitors produce pulmonary antiinflammatory effects in rats. Furthermore, these results suggest that PDE3 inhibitors also can produce pulmonary antiinflammatory effects in vivo.
Howell
R E
RE
Inflammatory Diseases Division, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000, USA.
Jenkins
L P
LP
Fielding
L E
LE
Grimes
D
D
D000628:Aminophylline / Q000494:pharmacology*; D000818:Animals; D007964:Leukocytosis / Q000517:prevention & control; D008297:Male; D009504:Neutrophils / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000517:prevention & control*; D011688:Purinones / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D020889:Rolipram
D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011760:Pyrrolidinones; D000628:Aminophylline; C011145:zaprinast; D020889:Rolipram