Role of contractile prostaglandins and Rho-kinase in growth factor-induced airway smooth muscle contraction

Schaafsma Dedmer, Gosens Reinoud, Bos, Meurs Herman, Zaagsma Johan, Nelemans

Description

In addition to their proliferative and differentiating effects, several growth factors are capable of inducing a sustained airway smooth muscle (ASM) contraction. These contractile effects were previously found to be dependent on Rho-kinase and have also been associated with the production of eicosanoids. However, the precise mechanisms underlying growth factor-induced contraction are still unknown. In this study we investigated the role of contractile prostaglandins and Rho-kinase in growth factor-induced ASM contraction. Methods Growth factor-induced contractions of guinea pig open-ring tracheal preparations were studied by isometric tension measurements. The contribution of Rho-kinase, mitogen-activated protein kinase (MAPK) and cyclooxygenase (COX) to these reponses was established, using the inhibitors Y-27632 (1 μM), U-0126 (3 μM) and indomethacin (3 μM), respectively. The Rho-kinase dependency of contractions induced by exogenously applied prostaglandin F 2α (PGF 2α ) and prostaglandin E 2 (PGE 2 ) was also studied. In addition, the effects of the selective FP-receptor antagonist AL-8810 (10 μM) and the selective EP 1 -antagonist AH-6809 (10 μM) on growth factor-induced contractions were investigated, both in intact and epithelium-denuded preparations. Growth factor-induced PGF 2α -and PGE 2 -release in the absence and presence of Y-27632, U-0126 and indomethacin, was assessed by an ELISA-assay. Results Epidermal growth factor (EGF)-and platelet-derived growth factor (PDGF)-induced contractions of guinea pig tracheal smooth muscle preparations were dependent on Rho-kinase, MAPK and COX. Interestingly, growth factor-induced PGF 2α -and PGE 2 -release from tracheal rings was significantly reduced by U-0126 and indomethacin, but not by Y-27632. Also, PGF 2α -and PGE 2 -induced ASM contractions were largely dependent on Rho-kinase, in contrast to other contractile agonists like histamine. The FP-receptor antagonist AL-8810 (10 μM) significantly reduced (approximately 50 %) and the EP 1 -antagonist AH-6809 (10 μM) abrogated growth factor-induced contractions, similarly in intact and epithelium-denuded preparations. Conclusion The results indicate that growth factors induce ASM contraction through contractile prostaglandins – not derived from the epithelium – which in turn rely on Rho-kinase for their contractile effects.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2005
• Nombre de lectures: 6
• Langue: English

Extrait

Respiratory Research

BioMedCentral

Open Access Research Role of contractile prostaglandins and Rho-kinase in growth factor-induced airway smooth muscle contraction Dedmer Schaafsma*, Reinoud Gosens, I Sophie T Bos, Herman Meurs, Johan Zaagsma and S Adriaan Nelemans

Address: Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands Email: Dedmer Schaafsma*  [e-mail]; Reinoud Gosens  [e-mail]; I Sophie T Bos  [e-mail]; Herman Meurs  [e-mail]; Johan Zaagsma  [e-mail]; S Adriaan Nelemans  [e-mail] * Corresponding author

Published: 27 July 2005 Received: 13 May 2005 Accepted: 27 July 2005 Respiratory Research2005,6:85 doi:10.1186/1465-9921-6-85 This article is available from: http://respiratory-research.com/content/6/1/85 © 2005 Schaafsma et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background:In addition to their proliferative and differentiating effects, several growth factors are capable of inducing a sustained airway smooth muscle (ASM) contraction. These contractile effects were previously found to be dependent on Rho-kinase and have also been associated with the production of eicosanoids. However, the precise mechanisms underlying growth factor- induced contraction are still unknown. In this study we investigated the role of contractile prostaglandins and Rho-kinase in growth factor-induced ASM contraction. Methods:Growth factor-induced contractions of guinea pig open-ring tracheal preparations were studied by isometric tension measurements. The contribution of Rho-kinase, mitogen-activated protein kinase (MAPK) and cyclooxygenase (COX) to these reponses was established, using the inhibitors Y-27632 (1µM), U-0126 (3µM) and indomethacin (3µM), respectively. The Rho-kinase dependency of contractions induced by exogenously app nd lied prostaglandin F 2
(PGF
) a 2 prostaglandin E (PGE ) was also studied. In addition, the effects of the selective FP-receptor 2 2 antagonist AL-8810 (10µM) and the selective EP -antagonist AH-6809 (10µM) on growth factor- 1 induced contractions were investigated, both in intact and epithelium-denuded preparations. Growth factor-induced P PGE -re GF
-and 2 lease in the absence and presence of Y-27632, U-0126 2 and indomethacin, was assessed by an ELISA-assay. Results:Epidermal growth factor (EGF)-and platelet-derived growth factor (PDGF)-induced contractions of guinea pig tracheal smooth muscle preparations were dependent on Rho-kinase, E elease from tracheal rings MAPK and COX. Interestingly, growth factor-induced PGF
-and PG 2 -r 2 was significantly reduced by U-0126 and indomethacin, but not by Y-27632. Also, PGF and PGE - 2
- 2 induced ASM contractions were largely dependent on Rho-kinase, in contrast to other contractile agonists like histamine. The FP-receptor antagonist AL-8810 (10µM) significantly reduced (approximately 50 %) and the EP -antagonist AH-6809 (10µM) abrogated growth factor-induced 1 contractions, similarly in intact and epithelium-denuded preparations.

Conclusion:The results indicate that growth factors induce ASM contraction through contractile prostaglandins – not derived from the epithelium – which in turn rely on Rho-kinase for their contractile effects.

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