PHARMACOLOGICAL MODULATION OF IMMEDIATE AND LATE AIRWAY RESPONSE AND LEUKOCYTE INFILTRATION IN THE GUINEA-PIG

We established an experimental model of late asthmatic response (LAR) using conscious guinea pigs actively sensitized by antigen aerosol inh alation. In actively sensitized guinea pigs, antigen challenge by aero sol inhalation caused an immediate increase in specific airway resista nce (sR(aw)) (immediate airway response; IAR) followed by a LAR which occurred 4 to 8 hr after antigen challenge. SR(aw) in the challenged a nimals was still increased 23 hr after antigen challenge. Examination of bronchoalveolar lavage (BAL) fluid and histology of the lungs revea led increases in eosinophils and neutrophils during LAR. The beta-2 ag onist salbutamol inhibited only IAR and not LAR. Dexamethasone inhibit ed LAR but not IAR. A low dose of theophylline had little effect on bo th IAR and LAR. A novel thromboxane A(2) (TXA2) receptor antagonist, A A-2414, orally administered before antigen challenge dose-dependently inhibited both IAR and LAR, and oral administration of AA-2414 after t he IAR inhibited LAR. Also, thromboxane synthetase inhibitors, CV-4151 and OKY-046, reduced both IAR and LAR. Salbutamol significantly reduc ed the increase in neutrophils in BAL fluid, and dexamethasone signifi cantly reduced the increase in eosinophils and neutrophils in BAL flui d. Theophylline also reduced the increase in eosinophils in BAL fluid. However, AA-2414 did not inhibit the accumulation of these inflammato ry cells in BAL fluid or the airway tissues. These results suggest tha t asthmatic responses in guinea pigs are similar to those in asthmatic subjects and that TXA(2) plays an important role in both IAR and LAR but not in inflammatory cell infiltration in this model of allergic as thma.