In vitro induced airway hyperresponsiveness

The isolated human bronchus model is interesting for the study of drug-rece ptor interactions in 'normal' preparations. Several attempts have been made to prepare in vitro models of airway hyperresponsiveness close to the path ophysiology of asthma. In this paper, we shall present some results obtained with LPS and interleu kin 1 beta (IL-1 beta). LPS (100 ng/ml, for 3 to 6 h) or IL-1 beta potentia ted bradykinin and the tachykinin NK-1 selective receptor agonist [Sar(9), Met-O-2] SP -induced human isolated bronchi contraction in vitro (IL-1 beta 3 10(-10) M, at 37 degrees C for 1 to 3 h for bradykinin or at 21 degrees C for 15 h for [Sar(9), Met-O-2] SP in Krebs-Henseleit solution). As in con trol bronchi, the effects of bradykinin and of [Sar(9), Met-O-2] SP after i nterleukin 1 beta pre-treatment were abolished by indomethacin (10(-6) M), the thromboxane A(2) receptor antagonist GR 32191 suggesting that prostanoi ds remain involved under these experimental conditions. Although bradykinin and [Sar(9), Met-O-2] SP -induced contractions were mediated by thromboxan e receptor stimulation, the thromboxane A(2) (TxA(2)) mimetic U46619 induce d contraction of human bronchi was not enhanced by IL-1 beta pre-treatment. The cyclooxygenase 2.(cox-2) inhibitor CGP 28238 (10(-6) M) inhibited IL-1 beta-induced potentiation of [Sar(9), Met-O-2] SP but not of bradykinin ef fect. Bradykinin and [Sar(9), Met-O-2] SP induced a release of TxB(2), the stable metabolite of TxA(2), in the organ bath and this release was increas ed by IL-1 beta pre-treatment. Bradykinin-induced release of 6 keto prostag landin F-1 alpha, (the stable metabolite of prostaglandin IQ) Was not enhan ced by IL-1 beta. Taken together, our results suggest that IL-1 beta is abl e to potentiate the effect of bradykinin or tachykinin receptor agonists on the human isolated bronchus. Several mechanisms might be involved, includi ng an increase of thromboxane synthase synthesis and/or activity in the cas e of bradykinin and of short term incubation (3 h, 37 degrees C) or an incr ease of synthesis and/or activity of cox-2 for tachykinin and for long-term incubation (15 h, 21 degrees C).