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

Eur J Pharmacol. 1999 Aug 20;379(1):87-95. doi: 10.1016/s0014-2999(99)00484-7.


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.

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
  • Aged
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Biphenyl Compounds / pharmacology
  • Bronchi / drug effects*
  • Cyclooxygenase Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Hypersensitivity / etiology
  • Drug Hypersensitivity / pathology*
  • Female
  • Heptanoic Acids / pharmacology
  • Humans
  • In Vitro Techniques
  • Indans / pharmacology
  • Indomethacin / pharmacology
  • Interleukin-1 / pharmacology*
  • Male
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects*
  • Prostaglandin Antagonists / pharmacology
  • Receptors, Tachykinin / drug effects
  • Substance P / pharmacology*
  • Thromboxane B2 / metabolism
  • Time Factors
  • Vasoconstrictor Agents / pharmacology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Biphenyl Compounds
  • Cyclooxygenase Inhibitors
  • Heptanoic Acids
  • Indans
  • Interleukin-1
  • Prostaglandin Antagonists
  • Receptors, Tachykinin
  • Vasoconstrictor Agents
  • Substance P
  • Thromboxane B2
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • flosulide
  • vapiprost
  • Indomethacin