Modulation of eotaxin formation and eosinophil migration by selective inhibitors of phosphodiesterase type 4 isoenzyme.
1. This study was undertaken to investigate the possible contribution of the blockade of eotaxin generation to the anti-eosinophilotactic effect of phosphodiesterase (PDE) type 4 inhibitors. In some experiments, the putative synergistic interaction between PDE type 4 inhibitors and the beta2-agonist salbutamol was also assessed. 2. Sensitized guinea-pigs aerosolized with antigen (5% ovalbumin, OVA) responded with a significant increase in eotaxin and eosinophil levels in the bronchoalveolar lavage fluid (BALF) at 6 h. Eosinophil recruitment was inhibited by both PDE type 4 inhibitors rolipram (5 mg kg(-1), i.p.) and RP 73401 (5 mg kg(-1), i.p.) treatments. In contrast, only rolipram inhibited eotaxin production. 3. Sensitized rats intrapleurally challenged (i.pl.) with antigen (OVA, 12 microg cavity(-1)) showed a marked eosinophil infiltration at 24 h, preceded by eotaxin generation at 6 h. Intravenous administration of a rabbit anti-mouse eotaxin antibody (0.5 mg kg(-1)) significantly reduced allergen-evoked eosinophilia in this model. 4. Local pretreatment with rolipram (40 microg cavity(-1)) or RP 73401 (40 microg cavity(-1)) 1 h before challenge reduced eosinophil accumulation evaluated in the rat pleural effluent, but only the former was active against eotaxin generation. The inhibitors of PDE type 3 (SK&F 94836) and type 5 (zaprinast) failed to alter allergen-evoked eosinophil recruitment in rats. 5. Local injection of beta2-agonist salbutamol (20 microg cavity(-1)) inhibited both eosinophil accumulation and eotaxin production following pleurisy. The former was better inhibited when salbutamol and rolipram were administered in combination. 6. Treatment with rolipram and RP 73401 dose-dependently inhibited eosinophil adhesion and migration in vitro. These effects were clearly potentiated by salbutamol at concentrations that had no effect alone. 7. Our findings indicate that although rolipram and RP 73401 are equally effective in inhibiting allergen-induced eosinophil infiltration only the former prevents eotaxin formation, indicating that PDE 4 inhibitors impair eosinophil accumulation by mechanisms independent of eotaxin production blockade.
Silva
P M
PM
Departmento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, FIOCRUZ, Av. Brasil. patmar@ioc.fiocruz.br
Alves
A C
AC
Serra
M F
MF
Pires
A L
AL
Silva
J P
JP
Barreto
E O
EO
Cordeiro
R S
RS
Jose
P J
PJ
Teixeira
M M
MM
Lagente
V
V
Martins
M A
MA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000485:Allergens / Q000276:immunology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006168:Guinea Pigs; D007106:Immune Sera / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010998:Pleurisy / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology; D044005:Tetrahydroisoquinolines
D000318:Adrenergic beta-Agonists; D000485:Allergens; D001549:Benzamides; C515457:Ccl11 protein, mouse; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D007106:Immune Sera; D007527:Isoenzymes; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D044005:Tetrahydroisoquinolines; C035964:trequinsin; D010047:Ovalbumin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D000420:Albuterol; C087566:piclamilast