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Eur J Pharmacol. 2000 Sep 8;403(3):267-75.

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

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Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Japan.


We examined the role of cyclooxygenase in airway hyperresponsiveness and inflammation after ozone exposure in guinea pigs using a non-selective (indomethacin) and a selective (JTE-522) cyclooxygenase-2 inhibitor. Spontaneously breathing guinea pigs were exposed to ozone (3 ppm) for 2 h after treatment with vehicle, indomethacin (10 mg/kg) or JTE-522 (10 mg/kg). Airway responsiveness to inhaled histamine (PC(200)) and bronchoalveolar lavage were assessed before, immediately and 5 h after ozone exposure. Ozone caused a significant airway hyperresponsiveness immediately after exposure, which persisted after 5 h. Neither JTE-522 nor indomethacin affected airway hyperresponsiveness immediately after ozone exposure, but significantly attenuated airway hyperresponsiveness 5 h after exposure, suggesting that cyclooxygenase-2 may participate in the late phase of airway hyperresponsiveness but not in the early phase. Ozone caused a significant increase in the concentration of prostaglandin E(2) and thromboxane B(2) in bronchoalveolar lavage fluid immediately after exposure, which decreased to the basal level 5 h after exposure. This increase in prostaglandin E(2) and thromboxane B(2) was significantly inhibited by JTE-522. An expression of cyclooxygenase-2 was detected not only after ozone exposure but also before, and there was no difference in the number of cyclooxygenase-2-positive cells at any time point. An exogenously 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 prostaglandin E(2) and thromboxane A(2) transiently under ozone stimulation and that thromboxane A(2) may, in turn, induce the late phase of airway hyperresponsiveness.

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