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Am J Physiol Lung Cell Mol Physiol 275: L322-L329, 1998;
1040-0605/98 $5.00
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Vol. 275, Issue 2, L322-L329, August 1998

Impaired cAMP production in human airway smooth muscle cells by bradykinin: role of cyclooxygenase products

Linhua Pang, Elaine Holland, and Alan J. Knox

Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham NG5 1PB, United Kingdom

Interleukin (IL)-1beta impairs human airway smooth muscle (ASM) cell cAMP responses to isoproterenol (Iso). We investigated if bradykinin (BK) could cause a similar effect and the role of cyclooxygenase (COX) products in this event, since we have recently reported that BK, like IL-1beta , also causes COX-2 induction and prostanoid release in human ASM cells. BK pretreatment significantly attenuated Iso-induced cAMP generation in a time- and concentration-dependent manner. cAMP generation by prostaglandin (PG) E2 but not by forskolin was also impaired. The COX inhibitor indomethacin completely prevented the impairment, whereas the selective COX-2 inhibitors NS-398 and nimesulide, protein synthesis inhibitors cycloheximide and actinomycin D, and steroid dexamethasone were all partially effective. The impairment was mimicked by the B2 agonist [Tyr(Me)8]BK, the Ca2+ ionophore A-23187, and PGE2 and prevented by the B2 antagonist HOE-140, but anti-IL-1beta serum was ineffective. The results indicate that BK impairs human ASM cell responses to Iso, and the effect is largely mediated by B2 receptor-related COX product release via both COX isoforms and is independent of IL-1beta .

airway inflammation; prostaglandin E2; asthma; cyclooxygenase induction; isoproterenol; adenosine 3',5'-cyclic monophosphate


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