Cyclooxygenase-2 participates in the late phase of airway hyperresponsiveness after ozone exposure in guinea pigs

We examined the role of cyclooxygenase in airway hyperresponsiveness and in flammation after ozone exposure in guinea pigs using a non-selective (indom ethacin) and a selective (JTE-522) cyclooxygenase-2 inhibitor. Spontaneousl y breathing guinea pigs were exposed to ozone (3 ppm) for 2 h after treatme nt with vehicle, indomethacin (10 mg/kg) or JTE-522 (10 mg/kg). Airway resp onsiveness to inhaled histamine (PC200) and bronchoalveolar lavage were ass essed before, immediately and 5 h after ozone exposure. Ozone caused a sign ificant airway hyperresponsiveness immediately after exposure, which persis ted after 5 h. Neither JTE-522 nor indomethacin affected airway hyperrespon siveness immediately after ozone exposure, but significantly attenuated air way hyperresponsiveness 5 h after exposure, suggesting that cyclooxygenase- 2 may participate in the late phase of airway hyperresponsiveness but not i n the early phase. Ozone caused a significant increase in the concentration of prostaglandin E-2 and thromboxane B-2 in bronchoalveolar lavage fluid i mmediately after exposure, which decreased to the basal level 5 h after exp osure. This increase in prostaglandin E-2 and thromboxane B-2 was significa ntly inhibited by JTE-522. An expression of cyclooxygenase-2 was detected n ot only after ozone exposure but also before, and there was no difference i n the number of cyclooxygenase-2-positive cells at any time point. An exoge nously applied thromboxane A(2) mimetic, U-46619 (10(-5) M), induced airway hyperresponsiveness 5 h after inhalation, but not immediately or 3 h after inhalation. These data suggest that cyclooxygenase-2 may be constitutively expressed before ozone exposure in guinea pig airway and may synthesize pr ostaglandin E-2 and thromboxane A(2) transiently under ozone stimulation an d that thromboxane A(2) may, in turn, induce the late phase of airway hyper responsiveness. (C) 2000 Elsevier Science B.V. All rights reserved.