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T Matsumoto, Y Ashida and R Tsukuda
Pharmaceutical Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
We established an experimental model of late asthmatic response (LAR) using conscious guinea pigs actively sensitized by antigen aerosol inhalation. In actively sensitized guinea pigs, antigen challenge by aerosol inhalation caused an immediate increase in specific airway resistance (SRaw) (immediate airway response; IAR) followed by a LAR which occurred 4 to 8 hr after antigen challenge. SRaw in the challenged animals was still increased 23 hr after antigen challenge. Examination of bronchoalveolar lavage (BAL) fluid and histology of the lungs revealed increases in eosinophils and neutrophils during LAR. The beta-2 agonist salbutamol inhibited only IAR and not LAR. Dexamethasone inhibited LAR but not IAR. A low dose of theophylline had little effect on both IAR and LAR. A novel thromboxane A2 (TXA2) receptor antagonist, AA-2414, orally administered before antigen challenge dose-dependently inhibited both IAR and LAR, and oral administration of AA-2414 after the IAR inhibited LAR. Also, thromboxane synthetase inhibitors, CV-4151 and OKY-046, reduced both IAR and LAR. Salbutamol significantly reduced the increase in neutrophils in BAL fluid, and dexamethasone significantly reduced the increase in eosinophils and neutrophils in BAL fluid. Theophylline also reduced the increase in eosinophils in BAL fluid. However, AA-2414 did not inhibit the accumulation of these inflammatory cells in BAL fluid or the airway tissues. These results suggest that asthmatic responses in guinea pigs are similar to those in asthmatic subjects and that TXA2 plays an important role in both IAR and LAR but not in inflammatory cell infiltration in this model of allergic asthma.
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