Pang L, Knox A J
Division of Respiratory Medicine, City Hospital, University of Nottingham, United Kingdom.
Am J Physiol. 1997 Dec;273(6):L1132-40. doi: 10.1152/ajplung.1997.273.6.L1132.
Prostanoids may be involved in bradykinin (BK)-induced bronchoconstriction in asthma. We investigated whether cyclooxygenase (COX)-2 induction was involved in prostaglandin (PG) E2 release by BK in cultured human airway smooth muscle (ASM) cells and analyzed the BK receptor subtypes responsible. BK stimulated PGE2 release, COX activity, and COX-2 induction in a concentration- and time-dependent manner. It also time dependently enhanced arachidonic acid release. In short-term (15-min) experiments, BK stimulated PGE2 generation but did not increase COX activity or induce COX-2. In long-term (4-h) experiments, BK enhanced PGE2 release and COX activity and induced COX-2. The long-term responses were inhibited by the protein synthesis inhibitors cycloheximide and actinomycin D and the steroid dexamethasone. The effects of BK were mimicked by the B2-receptor agonist [Tyr(Me)8]BK, whereas the B1 agonist des-Arg9-BK was weakly effective at high concentrations. The B2 antagonist HOE-140 potently inhibited all the effects, but the B1 antagonist des-Arg9,(Leu8)-BK was inactive. This study is the first to demonstrate that BK can induce COX-2. Conversion of increased arachidonic acid release to PGE2 by COX-1 is mainly involved in the short-term effect, whereas B2 receptor-related COX-2 induction is important in the long-term PGE2 release.
前列腺素类物质可能参与哮喘中缓激肽（BK）诱导的支气管收缩。我们研究了环氧化酶（COX）-2的诱导是否参与BK在培养的人气道平滑肌（ASM）细胞中释放前列腺素（PG）E2，并分析了负责的BK受体亚型。BK以浓度和时间依赖性方式刺激PGE2释放、COX活性和COX-2诱导。它还随时间依赖性地增强花生四烯酸释放。在短期（15分钟）实验中，BK刺激PGE2生成，但不增加COX活性或诱导COX-2。在长期（4小时）实验中，BK增强PGE2释放和COX活性并诱导COX-2。长期反应受到蛋白质合成抑制剂放线菌酮和放线菌素D以及类固醇地塞米松的抑制。BK的作用被B2受体激动剂[酪氨酸（甲基）8]BK模拟，而B1激动剂去-精氨酸9-BK在高浓度时效果较弱。B2拮抗剂HOE-140有效抑制所有作用，但B1拮抗剂去-精氨酸9，（亮氨酸8）-BK无活性。本研究首次证明BK可诱导COX-2。COX-1将增加的花生四烯酸释放转化为PGE2主要参与短期效应，而B2受体相关的COX-2诱导在长期PGE2释放中很重要。
