In vitro-induced human airway hyperresponsiveness to bradykinin

Lipopolysaccharide (LPS) and interleukin (IL)-1 beta have been reported to induce airway hyperresponsiveness in several animal models. This study inve stigated the effect of LPS or IL-1 beta on bradykinin-induced human isolate d bronchi contraction. LPS (100 ng.mL(-1) for 3-6 h) and IL-1 beta (3x10(-10) and 3x10(-9) M for 2 0 min to 3 h) time-dependently potentiated bradykinin-induced contraction. This contraction was abolished, as in control experiments, by indomethacin (10(-6) M) or by the thromboxane (Tx) receptor antagonist GR 32191 but not by the cyclo-oxygenase-2 inhibitor, CGP28238, In contrast, the Tx mimetic U 46619-induced contraction of human bronchi was not enhanced by IL-1 beta pr etreatment, In the presence of CR 32191 (10(-6) M), bradykinin induced a pr ostanoid dependent relaxation that was not significantly modified by IL-1 b eta pretreatment, Determination of prostanoids in the organ bath fluid show ed that bradykinin induced TxB(2) the stable metabolite of TxA(2) and 6-ket o prostaglandin F-1 alpha, the stable metabolite of PGI(2), release. Only T xA(2) release was potentiated by IL-1 beta. Taken together our results suggest that interleukin-1 beta (1-3 h)-induced potentiation of the effect of bradykinin is linked to an increased activity of thromboxane synthase and, in turn, to increased thromboxane synthesis.