Interleukin-1 beta-induced hyperresponsiveness to [Sar(9),Met(O-2)(11)]substance P in isolated human bronchi

Interleukin-1 beta has been reported to induce airway hyperresponsiveness i n several animal models. In this study, we have investigated whether interl eukin-1 beta was able to potentiate the contractions of human isolated smal l bronchi (internal diameter less than or equal to 1 mm) provoked by a spec ific tachykinin NK1 receptor agonist, [Sar(9),Met(O-2)(11)]substance P. Pre -incubation of human isolated small bronchi with interleukin-1 beta (10 ng/ ml, in Krebs-Henseleit solution, at 21 degrees C for 15 h) potentiated the contractile response to [Sar(9),Met(O-2)(11)]substance P. It also increased the [Sar(9),Met(O-2)(11)]substance P-induced release of thromboxane B-2 th e stable metabolite of thromboxane A(2). Indomethacin (10(-6) M), a non-spe cific cyclooxygenase inhibitor, or GR 32191 ((1R-(1 alpha(Z),2 beta,3 beta, 5 alpha))-(+)-7-(5-(((1,1'-biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidi nyl)cyclopentyl)-4- acid, hydrochloride) (10(-6) M), a prostanoid TP-recept or antagonist, blocked the contractions induced by [Sar(9),Met(O-2)(11)]sub stance P both in control experiments and after interleukin-1 beta pre-treat ment, indicating that prostanoids and thromboxane receptors are directly im plicated in the [Sar(9),Met(O-2)(11)]substance P-induced contractile respon se. The thromboxane mimetic U-46619 (10(-8)-10(-6) M) (9,11-dideoxy-11 alph a,9 alpha-epoxymethano-prostaglandin F-2 alpha)-induced contractions of hum an isolated small bronchi were not enhanced by interleukin-1 beta pre-treat ment, suggesting that no up-regulation of thromboxane receptors occurred. F urthermore, the cyclooxygenase-2 inhibitor CGP 28238 (6-(2,4-difluorophenox y)-5-methyl-sulfonylamino-1-indanone) (10(-6) M) had no direct effect on [S ar(9),Met(O-2)(11)]substance P-provoked contractions, but inhibited the int erleukin-1 beta-induced potentiation of [Sar(9),Met(O-2)(11)]substance P re sponse. In conclusion, our results show that interleukin-1 beta pre-treatme nt is able to potentiate the contractions of isolated human small bronchi p rovoked by [Sar(9),Met(O-2)(11)]substance P both by increasing prostanoid s ynthesis and by inducing a cyclooxygenase-2 pathway. (C) 1999 Elsevier Scie nce B.V. All rights reserved.