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

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Abstract

Interleukin-1β has been reported to induce airway hyperresponsiveness in several animal models. In this study, we have investigated whether interleukin-1β was able to potentiate the contractions of human isolated small bronchi (internal diameter ≤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-1β (10 ng/ml, in Krebs–Henseleit solution, at 21°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-(1α(Z),2β,3β,5α))-(+)-7-(5-(((1,1′-biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic 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-1β 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-11α,9α-epoxymethano-prostaglandin F)-induced contractions of human isolated small bronchi were not enhanced by interleukin-1β 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-indanone) (10−6 M) had no direct effect on [Sar9,Met(O2)11]substance P-provoked contractions, but inhibited the interleukin-1β-induced potentiation of [Sar9,Met(O2)11]substance P response. In conclusion, our results show that interleukin-1β 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.

Introduction

Airway inflammation, a main feature of asthma, is involved in the pathophysiology of airway hyperresponsiveness. Increased levels of several pro-inflammatory cytokines including interleukin-1β have been found in bronchoalveolar lavage fluid from symptomatic asthmatic patients (Broide et al., 1992; Cembrzynska-Nowak et al., 1993). Among the various endogenous inflammatory mediators and cytokines involved in airway inflammation, interleukin-1β has been shown to induce airway hyperresponsiveness in several models (Hernandez et al., 1991; Van Oosterhout and Nijkamp, 1993; Tsukagoshi et al., 1994; Molimard et al., 1998). The mechanisms of this hyperresponsiveness are unclear but may be mediated in part by prostanoids. Indeed, several studies have shown that prostanoid synthesis may be enhanced by interleukin-1β. Interleukin-1β is able to induce cyclooxygenase-2 production by cultured airway epithelial and smooth muscle cells and subsequently, increases the release of prostanoid into the culture medium (Mitchell et al., 1994; Belvisi et al., 1997; Pang and Knox, 1997). We have recently demonstrated that bradykinin-induced contraction of isolated human bronchi is enhanced by interleukin-1β through thromboxane synthase induction and subsequent increased thromboxane A2 release induced by bradykinin (Molimard et al., 1998).

Among contractile mediators involved in asthma, bradykinin exerts a contractile effect on isolated human bronchi indirectly through prostanoid release since it is abolished by the cyclooxygenase inhibitor, indomethacin (Molimard et al., 1994; Naline et al., 1996). A similar release of prostanoid has been described for substance P but its mechanism of action is more complex (Naline et al., 1996). Indeed, substance P has first been reported to induce at high concentrations a contraction of isolated human large bronchi through tachykinin NK2 receptor stimulation since its effect is abolished by the tachykinin NK2 receptor antagonist SR 48968 and not by the tachykinin NK1 receptor antagonist, CP 96345 (Naline et al., 1989; Advenier et al., 1992). We have more recently reported that on isolated human small bronchi (diameter <1 mm), substance P at low concentrations and some specific tachykinin NK1 receptor agonists, such as [Sar9,Met(O2)11]substance P, produce a concentration-dependent contraction through tachykinin NK1 receptor stimulation since it is abolished by the tachykinin NK1 receptor antagonist SR 140333 (Naline et al., 1996). Conversely to tachykinin NK2 receptor-mediated contraction, the tachykinin NK1-induced contraction is mediated by prostanoids, since it is abolished by indomethacin (Naline et al., 1996).

Since (1) tachykinin NK1 receptor stimulation may induce airway smooth muscle contraction through prostanoid release and (2) interleukin-1β may enhance prostanoid release, the aim of this study was to determine whether interleukin-1β induces hyperresponsiveness to a tachykinin NK1 receptor agonist on human bronchial tissue in vitro and if so, to determine the mechanism of this hyperresponsiveness.

Section snippets

Human bronchial tissue preparation

Bronchial tissues were removed from 28 patients (25 men and 3 women, mean age 66.2±1.7 years) with lung cancer at the time of the surgical operation. All were previous smokers. None was asthmatic. Just after resection, segments of bronchi were taken as far away as possible from the malignancy and were dissected free of parenchyma. After removal of adhering fat and connective tissues, small rings (inner diameter of 0.5 to 1 mm, 7 mm length) of the same human bronchus were placed in oxygenated

Influence of interleukin-1β pre-treatment on [Sar9,Met(O2)11]substance P-, acetylcholine- and the thromboxane mimetic U-46619-induced contraction of isolated human bronchi

On isolated human small bronchi (diameter <1 mm), [Sar9,Met(O2)11]substance P (10−7 M) induced a transient contraction (Fig. 1). Incubation of the bronchi in Krebs–Henseleit solution at room temperature (21°C) for 15 h did not alter the responsiveness to [Sar9, Met(O2)11]substance P. A pre-treatment with interleukin-1β (10 ng/ml, 15 h, 21°C) potentiated [Sar9,Met(O2)11]substance P-induced contractions (Fig. 2, Table 1). Interleukin-1β pre-treatment induced an increased response to [Sar9,Met(O2)

Discussion

Substance P, a neuropeptide of the tachykinin family is localized in the lung in the sensory unmyelinated C-fibers which innervate all compartments of the airway wall, from the trachea down to the bronchiole and is, along with neurokinins A and B and calcitonin gene related peptide (CGRP), a transmitter of the excitatory non-adrenergic non-cholinergic (NANC) system (Lembeck and Holzer, 1970; Lundberg and Saria, 1987; Ellis and Undem, 1994; Fischer et al., 1996; Lundberg, 1996). The stimulation

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