EFFECT OF A LEUKOTRIENE B-4 RECEPTOR ANTAGONIST SC-53228 ON OZONE-INDUCED AIRWAY HYPERRESPONSIVENESS AND INFLAMMATION IN DOGS

The importance of the potent neutrophil chemoattractant leukotriene (L T)B-4 in causing ozone-induced bronchoconstriction, airway inflammatio n, and airway hyperresponsiveness in dogs was studied using the LTB(4) -receptor antagonist SC-53228. Seven dogs from random sources were stu died three times, at least 2 wk apart. On each occasion, acetylcholine (Ach) airway responsiveness was measured before and 1 h after ozone ( 3 ppm, 30 min) or dry air inhalation, followed by a bronchoalveolar la vage (BAL). On the first day, dogs were treated with SC-53228 (0.4 mg/ kg intravenously) followed by a continuous intravenous infusion of 1.2 mg/kg/h before ozone inhalation. On the other two days, diluent was i nfused followed by ozone or dry air inhalation. Cell counts were measu red in BAL and cell activation was measured by spontaneous and by phor bol myristate acetate-stimulated (PMA) (2.4 mu mol/L;) oxygen radical release, measured from washed BAL cells (4 x 10(6) cells) by lucigenin -enhanced chemiluminescence. Ozone inhalation caused bronchoconstricti on and airway hyperresponsiveness. SC-53228 inhibited the ozone-induce d airway hyperresponsiveness (p = 0.006), but not the bronchoconstrict ion. Spontaneous (p = 0.004) and PMA-stimulated (p = 0.04) lucigenin-e nhanced chemiluminescence were increased after ozone inhalation. The o zone-induced increases in PMA-stimulated chemiluminescence were signif icantly attenuated by treatment with SC-53228 (p = 0.04). These result s suggest that LTB(4) is involved in the pathogenesis of ozone-induced airway hyperresponsiveness, possibly through activation of airway inf lammatory cell.