PDE4 inhibition and a corticosteroid in chronically antigen exposed conscious guinea-pigs.
BACKGROUND
The physiological and pharmacological consequences of repeated aero-allergen challenge have not been previously characterized in conscious, sensitized guinea-pigs.


OBJECTIVE
This study was undertaken to compare the effects of two anti-inflammatory compounds, dexamethasone and Ro 20- 1724, on an acute and chronic airway inflammation, in terms of airway function, reactivity and leucocyte infiltration.


METHODS
Sensitized guinea-pigs received eight saline or ovalbumin (OvA) inhalation exposures over 4 weeks and either vehicle, the type 4 PDE inhibitor, Ro 20-1724 (3 mgkg(-1)), or dexamethasone (1.5 mg/kg(-1)), 30 min before and 6 h after each challenge. Airway function of the conscious animal (sGaw) was monitored over the duration of the first and final OvA challenge. Airway reactivity to the thromboxane mimetic, U46619, was also determined following the final OvA exposure as was the leucocyte infiltration.


RESULTS
The first antigen challenge induced a large early (0-3h) and smaller late (17-24h) bronchoconstrictor response. Neither phase was affected by the drug treatments. The final OvA challenge induced early and late phase bronchoconstrictor responses but of similar magnitude. The late phase was also significantly prolonged. Ro 20-1724 and dexamethasone significantly attenuated both phases. Airway reactivity to the inhaled thromboxane mimetic, U46619, was also significantly enhanced at 120h after the final OvA exposure in contrast to the saline challenged group. This hyperreactivity was attenuated by Ro 20-1724 and dexamethasone. Bronchoalveolar lavage after repeated OvA exposures revealed eosinophilia which was attenuated by Ro 20-1724 and dexamethasone.


CONCLUSIONS
This model demonstrates differential airway responses to acute and chronic antigen challenge. Repeated administration of dexamethasone and Ro 20-1724 with each OvA exposure attenuated all of the chronic inflammatory responses: early and late phase responses, hyperreactivity and eosinophilia.
Danahay
H
H
Pharmacology Department, The Welsh School of Pharmacy, University of Wales, College of Cardiff, UK.
Broadley
K J
KJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000276:immunology / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology; D002452:Cell Count / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004802:Eosinophilia / Q000139:chemically induced / Q000276:immunology; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology*; D006168:Guinea Pigs; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000276:immunology / Q000494:pharmacology
D000941:Antigens; D005938:Glucocorticoids; D010726:Phosphodiesterase Inhibitors; D014662:Vasoconstrictor Agents; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003907:Dexamethasone; D010047:Ovalbumin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4