[Approach to bronchial hyperreactivity in vitro].
The isolated human bronchus model is interesting for the study of drug-receptor interactions in 'normal' preparations. Several attempts have been made to prepare in vitro models of airway hyperresponsiveness close to the pathophysiology of asthma. In this paper, we shall present some results obtained with LPS and interleukin 1 beta (IL-1 beta). LPS (100 ng/ml, for 3 to 6 h) or IL-1 beta potentiated bradykinin and the tachykinin NK-1 selective receptor agonist [Sar9, Met-O2] 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 [Sar9, Met-O2] SP in Krebs-Henseleit solution). As in control bronchi, the effects of bradykinin and of [Sar9, Met-O2] SP after interleukin 1 beta pre-treatment were abolished by indomethacin (10(-6) M), the thromboxane A2 receptor antagonist GR 32191 suggesting that prostanoids remain involved under these experimental conditions. Although bradykinin and [Sar9, Met-O2] SP -induced contractions were mediated by thromboxane receptor stimulation, the thromboxane A2 (TxA2) mimetic U46619 induced contraction of human bronchi was not enhanced by IL-1 beta pre-treatment. The cyclooxygenase 2 (cox 2) inhibitor GGP 28238 (10(-6) M) inhibited IL-1 beta-induced potentiation of [Sar9, Met-O2] SP but not of bradykinin effect. Bradykinin and [Sar9, Met-O2] SP induced a release of TxB2, the stable metabolite of TxA2, in the organ bath and this release was increased by IL-1 beta pre-treatment. Bradykinin-induced release of 6 keto prostaglandin F1 alpha (the stable metabolite of prostaglandin I2) was not enhanced by IL-1 beta. Taken together, our results suggest that IL-1 beta is able to potentiate the effect of bradykinin or tachykinin receptor agonists on the human isolated bronchus. Several mechanisms might be involved, including an increase of thromboxane synthase synthesis and/or activity in the case of bradykinin and of short term incubation (3 h, 37 degrees C) or an increase of synthesis and/or activity of cox-2 for tachykinin and for long-term incubation (15 h, 21 degrees C).
Molimard
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Département de Pharmacologie, CHU Pellegrin-Carreire, Bordeaux, France.
Advenier
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D001249:Asthma / Q000503:physiopathology; D001920:Bradykinin / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007189:Indans; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D018040:Receptors, Neurokinin-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C059178:flosulide; D001920:Bradykinin