PGE2 release by bradykinin in human airway smooth muscle cells: involvement of cyclooxygenase-2 induction.
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.
Pang
L
L
Division of Respiratory Medicine, City Hospital, University of Nottingham, United Kingdom.
Knox
A J
AJ
D000328:Adult; D016718:Arachidonic Acid / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis*; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D018002:Receptors, Bradykinin / Q000819:agonists / Q000502:physiology; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D065168:Bradykinin Receptor Antagonists; D007527:Isoenzymes; D008565:Membrane Proteins; D018002:Receptors, Bradykinin; D016718:Arachidonic Acid; C051090:bradykinin, Leu(8)-des-Arg(9)-; C065679:icatibant; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001920:Bradykinin