PGE2release by bradykinin in human airway smooth muscle cells: involvement of cyclooxygenase-2 induction

Abstract

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 PGE₂release, 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 B₂antagonist 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.