Interleukin-1β-induced hyperresponsiveness to [Sar9, Met(O2)11]substance P in isolated human bronchi

Abstract Interleukin-1β has been reported to induce airway hyperresponsiveness in several animal models. In this study, we have investigated whether interleukin-1β was able to potentiate the contractions of human isolated small bronchi (internal diameter ≤1 mm) provoked by a specific tachykinin NK 1 receptor agonist, [Sar 9 ,Met(O 2 ) 11 ] substance P. Pre-incubation of human isolated small bronchi with interleukin-1β (10 ng/ml, in Krebs–Henseleit solution, at 21°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 thromboxaneB 2 , the stable metabolite of thromboxaneA 2 . Indomethacin (10 −6 M), a non-specific cyclooxygenaseinhibitor, or GR 32191 ((1 R -(1α( Z ),2β,3β,5α))-(+)-7-(5-(((1,1′-biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, hydrochloride) (10 −6 M), a prostanoidTP-receptor antagonist, blocked the contractions induced by [Sar 9 ,Met(O 2 ) 11 ] substance Pboth in control experiments and after interleukin-1β pre-treatment, indicating that prostanoidsand thromboxane receptorsare directly implicated in the [Sar 9 ,Met(O 2 ) 11 ] substance P-induced contractile response. The thromboxanemimetic U-46619 (10 −8 –10 −6 M) (9,11-dideoxy-11α,9α-epoxymethano-prostaglandin F 2α )-induced contractions of human isolated small bronchi were not enhanced by interleukin-1β pre-treatment, suggesting that no up-regulation of thromboxane receptorsoccurred. Furthermore, the cyclooxygenase-2 inhibitor CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanone) (10 −6 M) had no direct effect on [Sar 9 ,Met(O 2 ) 11 ] substance P-provoked contractions, but inhibited the interleukin-1β-induced potentiation of [Sar 9 ,Met(O 2 ) 11 ] substance Presponse. In conclusion, our results show that interleukin-1β pre-treatment is able to potentiate the contractions of isolated human small bronchi provoked by [Sar 9 ,Met(O 2 ) 11 ] substance Pboth by increasing prostanoidsynthesis and by inducing a cyclooxygenase-2 pathway.