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ENFUMOSA (courriel: Chanez (at) montp.inserm.fr ) The European Network For Understanding Mechanisms of Severe Asthma BIOMED 2 Program - European Commission 4th quaterly meeting, with the support of INSERM and Merck Sharp & Dhome Laboratory February 13-14th 1998 in Montpellier- France (see programm, abstracts and experts comments ) Influence of lipopolysaccharide (LPS) and interleukin 1-ß (IL1-ß) on human isolated bronchi responsiveness to bradykinin, substance-P and neurokinin A. Mathieu Molimard and Charles Advenier Dpt de Pharmacologie, Facultés de Médecine de Bordeaux (M.M) et de Paris-CHU Paris Ouest (C.A) Samedi 14 Février 1998 Présentateurs Modérateurs Experts 8h00-9h00 Muscle lisse Smooth muscle G. Advenier, M. Molimard (Paris) J.M. Tunon de Lara (Bordeaux) Discussion 15' 15' 30' R. Marthan (Bordeaux) J. Mercier (Montpellier) F.P. Nijkamp (Utrecht, NL) K. Rabe (Grossandorf, D) 1. Introduction Several studies have shown that airway smooth muscle cell, in addition to its contractile function, can be implicated in inflammatory reactions. In response to inflammatory cytokines, the airway smooth muscle cell produces cytokines, chemokines, growth factors, cell adhesion molecules, inducible enzyme or receptors… (Johnson and Knox, 1997). Incubation of human airway smooth muscle in serum of allergic patients is able to induce airway hyper responsiveness (Ben-Sebria et al.,). We have recently investigated whether LPS or IL-1ß were able to potentiate the human isolated bronchus response to bradykinin, substance P or neurokinin A and studied the mechanisms of these potentiations.

2. Responses to bradykinin (Molimard et al., 1997)

• 2.1. – LPS (100 ng/ml, during 3 to 6 hours) and IL-1ß (3 10^-10 M, at 37°C during 20 min. to 3 hours) time-dependently potentiated bradykinin-induced human isolated bronchi contraction in vitro. As in control bronchi, the effect of bradykinin after interleukin 1ß pretreatment was abolished by indomethacin (10^-6 M), the thromboxane A₂ antagonist GR 32191 and by the bradykinin B₂ receptor antagonist Hoe l40 (10^-6 M), suggesting that prostanoids and B₂ receptor remain involved in bradykinin's effect under these experimental conditions.
• 2.2. – Although bradykinin-induced contraction was mediated by thromboxane receptor stimulation, the thromboxane mimetic U46619 induced contraction of human bronchi was not enhanced by IL-1ß pretreatment. Furthermore, the cyclooxygenase 2 (cox-2) inhibitor CGP 28238 (10^-6 M) failed to inhibit IL-1ß-induced potentiation of bradykinin effect.
• 2.3. – Bradykinin, in control preparation, is able to induce a relaxation of human bronchi in the presence of the thromboxane receptor antagonist GR 32191. This response which is abolished by indomethacin in control bronchi is unmodified by IL-1ß pretreatment.
• 2.4. – Bradykinin induced thromboxane B₂ (the stable metabolite of thromboxane A₂) and 6 keto prostaglandin F1a (the stable metabolite of prostaglandin I₂) release in isolated human bronchi. The thromboxane B₂ release was potentiated by IL-1ß.

3. Responses to substance P and neurokinin A (Naline et al., 1998)

• 3.1. – In an other set of experiments we have investigated whether IL-1ß was able to potentiate the human isolated bronchus response to the tachykinin NK-1 selective receptor agonist ([Sar⁹, Met-O₂] SP). IL-1ß (3x10^-10 M, during 15 hours in Krebs-Henseleit solution, at 21 °C) potentiated [Sar⁹, Met-O₂] SP induced human isolated small bronchi (internal diameter ² 1 mm) contraction in vitro. The effect of ([Sar⁹, Met-O₂] SP in control experiments or after IL-1ß pretreatment was abolished by indomethacin (10^-6 M) and GR 32191 (10^-6 M) suggesting that prostanoids and TP receptor remain implicated in [Sar⁹, Met-O₂] SP effects under these experimental conditions. Furthermore, [Sar⁹, Met-O₂] SP induced a release of TXB₂, the metabolite of TXA₂, in the organ bath and this effects was increased by IL-1ß pretreatment. This suggest that in [Sar⁹, Met-O₂] SP-induced contraction is mediated by thromboxane receptor stimulation. The thromboxane mimetic U46619 induced contraction of human bronchi was not enhanced by IL-1ß pretreatment. In contrast to our observations with bradykinin, the cyclooxygenase 2 inhibitor CGP 28238 (10^-6 M) inhibit the IL-1ß induced potentiation of in [Sar⁹, Met-O₂] SP effect.
• 3.2. – Under similar condition (IL-1ß 3 x 10^-10 M, 15 h, 21 °C) the human isolated bronchus response to neurokinin A was only slightly potentiated whereas the response to bradykinin was unmodified.

4. Conclusions

Taken together, our results suggest that IL-1ß is able to potentiate the effect of bradykinin or tachykinin receptor agonists on the human isolated bronchus. However, 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 °C) or an increase of synthesis and/or activity of cycloxygenase-2 (Cox-2) in the case of tachykinin and for long term incubation (15h, 21 °C)

References

Ref (1): A. Ben-Jebria, R. Marthan, M. Rossetti, J.P. Savineau Effect of passive sensitization on the mechanical activity of human isolated bronchial smooth muscle induced by substance P, neurokinin A and VIP. Br. J. Pharmacol., 1993, 109, 131-136. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Ben-Jebria A; Marthan R; Rossetti M; Savineau JP
Address : Laboratoire de Physiologie, Faculté de Médecine Victor Pachon, Université de Bordeaux II, France.
Source : Br J Pharmacol, 109(1):131-6 1993 May
Abstract :
1. The effect of passive sensitization on the mechanical activity of human isolated bronchial smooth muscle induced by the following neuropeptides substance P (SP), neurokinin A (NKA) and vasoactive intestinal peptide (VIP) was studied both in the absence and in the presence of the neutral endopeptidase (NEP) inhibitor, phosphoramidon.

2. Cumulative concentration-response curves (CCRC) to these neuropeptides were constructed in human passively sensitized isolated bronchial rings and compared to those in paired controls. Passively sensitized human isolated bronchial rings were tissues incubated overnight in serum from asthmatic patients atopic to Dermatophagoides pteronyssinus and paired controls were tissues originating from the same lung specimens but incubated overnight in serum from healthy donors.

3. In the absence of phosphoramidon, passive sensitization significantly increased the amplitude of the contractile responses to SP and NKA including that to the maximal concentration given from 50 +/- 5% to 76 +/- 6% (n = 5, P < 0.05) and from 70 +/- 7% to 101 +/- 6% (n = 5, P < 0.05) of the maximal response to acetylcholine, respectively....

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Ref (2): S.R. Johnson, A.J. Knox. Synthetic functions of airway smooth muscle in asthma TIPS, 1997, 18, 288-292. (partial abstract from http://www.healthy.net/library/search/medline.htm )

no abstract available

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Ref (3): M. Molimard, E.Naline, P. Devillier, E. Boichot, V. Lagente, C. Advenier. Human airway hyperresponsiveness to bradykinin induced by endotoxin and interleukin 1ß, in vitro. Am. J. Respir. Crit. Care Med., 1997, 155, A375. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Johnson SR; Knox AJ
Address : Division of Respiratory Medicine, City Hospital, Nottingham, UK.
Source : Trends Pharmacol Sci, 18(8):288-92 1997 Aug
Abstract : Studies now show that the airway smooth muscle cell, in addition to its contractile function, can participate in and coordinate the inflammatory response. In response to inflammatory cytokines, the airway smooth muscle cell produces cytokines, chemokines, growth factors and cell adhesion molecules leading to inflammatory cell chemotaxis, hyperplasia and hypertrophy. Anti-inflammatory mediators are also produced suggesting a dual role in inflammation. Moreover, in response to growth stimuli the cells may adopt a phenotype more suited to 'synthetic' function. These issues are discussed in this article by Simon Johnson and Alan Knox, who also point to ways in which some of these pathways offer future therapeutic potential in asthma.

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

Ref (4): E. Naline, E. Barchasz, M. Molimard, J. Morreau, X Emonds-Alt and C. Advenier. Interleukin 1ß induces an hyperresponsiveness of human isolated bronchi to in [Sar⁹, Met-O2] SP, a tachykinin NK-1 receptor agonist.Am. J. Resp. Crit. Care Med, 1998 (Abstract), in press. (partial abstract from http://www.healthy.net/library/search/medline.htm )

no abstract available

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Ref (5): D.N. Watkins, M.J. Garlepp, P.J. Thompson. Regulation of the inducible cyclo-oxygenase pathway in human cultured airway epithelial (A549) cells by nitric oxide. Br. J. Pharmacol., 1997, 121, 1482-1488.. (partial abstract from http://www.healthy.net/library/search/medline.htm )

none available

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Date de création: 5 Décembre 1997-Dernière mise à jour: 23/07/98
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