白细胞介素-1β诱导离体人支气管对[Sar9,Met(O2)11]P物质的高反应性。

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

作者信息

Barchasz E, Naline E, Molimard M, Moreau J, Georges O, Emonds-Alt X, Advenier C

机构信息

Pharmacologie, Faculté de Médecine Paris-Quest, Paris, France.

出版信息

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

DOI:10.1016/s0014-2999(99)00484-7

PMID:10499376

Abstract

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.

摘要

据报道，白细胞介素-1β可在多种动物模型中诱导气道高反应性。在本研究中，我们调查了白细胞介素-1β是否能够增强由特异性速激肽NK1受体激动剂[Sar9,Met(O2)11]P物质引发的人离体小支气管（内径≤1mm）的收缩。将人离体小支气管与白细胞介素-1β（10ng/ml，在Krebs-Henseleit溶液中，21℃孵育15小时）预孵育，可增强对[Sar9,Met(O2)11]P物质的收缩反应。它还增加了[Sar9,Met(O2)11]P物质诱导的血栓素B2（血栓素A2的稳定代谢产物）的释放。非特异性环氧化酶抑制剂吲哚美辛（10⁻⁶M）或前列腺素TP受体拮抗剂GR 32191（(1R-(1α(Z)),2β,3β,5α)-(+)-7-(5-(((1,1'-联苯)-4-基)-甲氧基)-3-羟基-2-(1-哌啶基)环戊基)-4-庚烯酸，盐酸盐）（10⁻⁶M）在对照实验和白细胞介素-1β预处理后均能阻断[Sar9,Met(O2)11]P物质诱导的收缩，表明前列腺素和血栓素受体直接参与了[Sar9,Met(O2)11]P物质诱导的收缩反应。血栓素类似物U-46619（10⁻⁸ - 10⁻⁶M）（9,11-二脱氧-11α,9α-环氧甲撑前列腺素F2α）诱导的人离体小支气管收缩未因白细胞介素-1β预处理而增强，提示血栓素受体未发生上调。此外，环氧化酶-2抑制剂CGP 28238（6-(2,4-二氟苯氧基)-5-甲基磺酰氨基-1-茚满酮）（10⁻⁶M）对[Sar9,Met(O2)11]P物质引发的收缩无直接影响，但可抑制白细胞介素-1β诱导的[Sar9,Met(O2)11]P物质反应增强。总之，我们的结果表明，白细胞介素-1β预处理能够通过增加前列腺素合成和诱导环氧化酶-2途径来增强[Sar9,Met(O2)11]P物质引发的离体人小支气管收缩。