Nakano H, Aizawa H, Matsumoto K, Fukuyama S, Inoue H, Hara N
Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Japan.
Eur J Pharmacol. 2000 Sep 8;403(3):267-75. doi: 10.1016/s0014-2999(00)00524-0.
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.
我们使用非选择性（吲哚美辛）和选择性（JTE - 522）环氧化酶 - 2抑制剂，研究了环氧化酶在豚鼠臭氧暴露后气道高反应性和炎症中的作用。用赋形剂、吲哚美辛（10毫克/千克）或JTE - 522（10毫克/千克）处理后，自主呼吸的豚鼠暴露于臭氧（3 ppm）中2小时。在臭氧暴露前、暴露后即刻和5小时评估气道对吸入组胺的反应性（PC20）和支气管肺泡灌洗情况。臭氧暴露后即刻引起显著的气道高反应性，5小时后仍持续存在。JTE - 522和吲哚美辛在臭氧暴露后即刻均未影响气道高反应性，但在暴露5小时后显著减轻了气道高反应性，这表明环氧化酶 - 2可能参与气道高反应性的后期阶段而非早期阶段。臭氧暴露后即刻导致支气管肺泡灌洗液中前列腺素E2和血栓素B2浓度显著升高，5小时后降至基础水平。JTE - 522显著抑制了前列腺素E2和血栓素B2的这种升高。不仅在臭氧暴露后检测到环氧化酶 - 2的表达，在暴露前也检测到，并且在任何时间点环氧化酶 - 2阳性细胞的数量均无差异。外源性应用血栓素A2模拟物U - 46619（10^(-5) M）在吸入后5小时诱导气道高反应性，但在吸入后即刻或3小时未诱导。这些数据表明，环氧化酶 - 2可能在豚鼠气道臭氧暴露前即组成性表达，并且在臭氧刺激下可能短暂合成前列腺素E2和血栓素A2，而血栓素A2可能继而诱导气道高反应性的后期阶段。
