PDE4 INHIBITION AND A CORTICOSTEROID IN CHRONICALLY ANTIGEN EXPOSED CONSCIOUS GUINEA-PIGS

Background. The physiological and pharmacological consequences of repe ated aeroallergen challenge have not been previously characterized in conscious, sensitized guinea-pigs. Objectives. This study was undertak en to compare the effects of two anti-inflammatory compounds, dexameth asone and Ro 20-1724, on an acute and chronic airway inflammation, in terms of airway function, reactivity and leucocyte infiltration. Metho ds. Sensitized guinea-pigs received eight saline or ovalbumin (OvA) in halation exposures over 4 weeks and either vehicle, the type 4 PDE inh ibitor, 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 consci ous animal (sG(aw)) was monitored over the duration of the first and f inal OvA challenge. Airway reactivity to the thromboxane mimetic, U466 19, was also determined following the final OvA exposure as was the le ucocyte infiltration. Results. The first antigen challenge induced a l arge early (0-3 h) and smaller lace (17-24 h) bronchoconstrictor respo nse. Neither phase was affected by the drug treatments. The final OvA challenge induced early and late phase bronchoconstrictor responses bu t of similar magnitude. The late phase was also significantly prolonge d. Ro 20-1724 and dexamethasone significantly attenuated both phases. Airway reactivity to the inhaled thromboxanemimetic, U46619, was also significantly enhanced at 120 h after the final OvA exposure in contra st to the saline challenged group. This hyperreactivity was attenuated by Ro 20-1724 and dexamethasone. Bronchoalveolar lavage after repeate d OvA exposures revealed eosinophilia which was attenuated by Ro 20-17 24 and dexamethasone. Conclusions. This model demonstrates differentia l airway responses to acute and chronic antigen challenge. Repeated ad ministration of dexamethasone and Ro 20-1724 with each OvA exposure at tenuted all of the chronic inflammatory responses: early and late phas e responses, hyperreactivity and eosinophilia.