Interleukin-1beta-induced hyperresponsiveness to [Sar9,Met(O2)11]substance P in isolated human bronchi.
Interleukin-1beta has been reported to induce airway hyperresponsiveness in several animal models. In this study, we have investigated whether interleukin-1beta was able to potentiate the contractions of human isolated small bronchi (internal diameter < or = 1 mm) provoked by a specific tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P. Pre-incubation of human isolated small bronchi with interleukin-1beta (10 ng/ml, in Krebs-Henseleit solution, at 21 degrees C for 15 h) potentiated the contractile response to [Sar9,Met(O2)11]substance P. It also increased the [Sar9,Met(O2)11]substance P-induced release of thromboxane B2, the stable metabolite of thromboxane A2. Indomethacin (10(-6) M), a non-specific cyclooxygenase inhibitor, or GR 32191 ((1R-(1alpha(Z)),2beta,3beta,5alpha))-(+)-7-(5-(((1,1' -biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-hept enoic acid, hydrochloride) (10(-6) M), a prostanoid TP-receptor antagonist, blocked the contractions induced by [Sar9,Met(O2)11]substance P both in control experiments and after interleukin-1beta pre-treatment, indicating that prostanoids and thromboxane receptors are directly implicated in the [Sar9,Met(O2)11]substance P-induced contractile response. The thromboxane mimetic U-46619 (10(-8)-10(-6) M) (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F2alpha)-induced contractions of human isolated small bronchi were not enhanced by interleukin-1beta pre-treatment, suggesting that no up-regulation of thromboxane receptors occurred. Furthermore, the cyclooxygenase-2 inhibitor CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanon e) (10(-6) M) had no direct effect on [Sar9,Met(O2)11]substance P-provoked contractions, but inhibited the interleukin-1beta-induced potentiation of [Sar9,Met(O2)11]substance P response. In conclusion, our results show that interleukin-1beta pre-treatment is able to potentiate the contractions of isolated human small bronchi provoked by [Sar9,Met(O2)11]substance P both by increasing prostanoid synthesis and by inducing a cyclooxygenase-2 pathway.
Barchasz
E
E
Pharmacologie, Faculté de Médecine Paris-Quest, Paris, France.
Naline
E
E
Molimard
M
M
Moreau
J
J
Georges
O
O
Emonds-Alt
X
X
Advenier
C
C
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000209:etiology / Q000473:pathology*; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D016861:Cyclooxygenase Inhibitors; D006538:Heptanoic Acids; D007189:Indans; D007375:Interleukin-1; D011448:Prostaglandin Antagonists; D018039:Receptors, Tachykinin; D014662:Vasoconstrictor Agents; D013373:Substance P; D013929:Thromboxane B2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C059178:flosulide; C060013:vapiprost; D007213:Indomethacin