QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.068387v1 311/1/402    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawabata, A. Articles by Saito, N. Search for Related Content PubMed PubMed Citation Articles by Kawabata, A. Articles by Saito, N.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Proteinase-Activated Receptor-2-Mediated Relaxation in Mouse Tracheal and Bronchial Smooth Muscle: Signal Transduction Mechanisms and Distinct Agonist Sensitivity

Division of Physiology and Pathophysiology, School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan (A.K., S.K., T.I., N.K., F.S., R.K.); Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (M.D.H.); and Tokyo New Drug Research Laboratories II, Pharmaceutical Division, Kowa Company Limited, Tokyo, Japan (T.K., N.S.)

We characterized the tracheal and bronchial relaxation caused by proteinase-activated receptor-2 (PAR-2) activation in ddY mice and/or in wild-type and PAR-2-knockout mice of C57BL/6 background. Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH₂) and Thr-Phe-Leu-Leu-Arg-amide, PAR-2- and PAR-1-activating peptides, respectively, caused relaxation in the isolated ddY mouse trachea and main bronchus. The relaxation was abolished by specific inhibitors of cyclooxygenase (COX)-1, COX-2, mitogen-activated protein kinase kinase (MEK), and p38 MAP kinase. The MEK and p38 MAP kinase inhibitors did not affect prostaglandin E₂-induced relaxation. Inhibitors of cytosolic Ca²⁺-dependent phospholipase A₂ (PLA), Ca²⁺-independent PLA₂, diacylglycerol lipase, tyrosine kinase, and protein kinase C exhibited no or only minor inhibitory effects on the PAR-mediated relaxation. Trypsin, a PAR-2 activator, and 2-furoyl-Leu-Ile-Gly-Arg-Leu-amide, a potent PAR-2-activating peptide, in addition to SLIGRL-NH₂, caused airway relaxation in wild-type C57BL/6 mice, as in ddY mice. In PAR-2-knockout mice, the peptide effects were absent and the potency of trypsin decreased. Desensitization of PAR-2 and/or PAR-1greatly suppressed the relaxant effect of trypsin. The bronchial and tracheal tissues displayed distinct sensitivities toward trypsin and the PAR-2-activating peptides. Our data indicate an involvement of both COX-1 and COX-2, and the MEK-extracellular signal-regulated kinase and p38 MAP kinase signaling pathways in the PAR-2- and PAR-1-triggered relaxation of mouse airway tissue, and substantiate a role for PAR-2 in regulating both the trachea and bronchial responsiveness in the mouse lung.

Address correspondence to: Atsufumi Kawabata, Division of Physiology and Pathophysiology, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. E-mail: kawabata{at}phar.kindai.ac.jp

This article has been cited by other articles:

				S. M. Saleh, T. S. Mann, T. Peters, R. J. Betts, and P. J. Henry Influence of Dexamethasone on Protease-Activated Receptor 2-Mediated Responses in the Airways J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 622 - 630. [Abstract] [Full Text] [PDF]

				J. Q. van der Merwe, M. D. Hollenberg, and W. K. MacNaughton EGF receptor transactivation and MAP kinase mediate proteinase-activated receptor-2-induced chloride secretion in intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, February 1, 2008; 294(2): G441 - G451. [Abstract] [Full Text] [PDF]

				E. Carrier, I. Brochu, A. J. de Brum-Fernandes, and P. D'Orleans-Juste The Inducible Nitric-Oxide Synthase Modulates Endothelin-1-Dependent Release of Prostacyclin and Inhibition of Platelet Aggregation ex Vivo in the Mouse J. Pharmacol. Exp. Ther., December 1, 2007; 323(3): 972 - 978. [Abstract] [Full Text] [PDF]

				S. KUBO, T. ISHIKI, I. DOE, F. SEKIGUCHI, H. NISHIKAWA, K. KAWAI, H. MATSUI, and A. KAWABATA Distinct Activity of Peptide Mimetic Intracellular Ligands (Pepducins) for Proteinase-Activated Receptor-1 in Multiple Cells/Tissues Ann. N.Y. Acad. Sci., December 1, 2006; 1091(1): 445 - 459. [Abstract] [Full Text] [PDF]

				R. W. Balzary and T. M. Cocks Lipopolysaccharide Induces Epithelium- and Prostaglandin E2-Dependent Relaxation of Mouse Isolated Trachea through Activation of Cyclooxygenase (COX)-1 and COX-2 J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 806 - 812. [Abstract] [Full Text] [PDF]

				N. Kawao, M. Nagataki, K. Nagasawa, S. Kubo, K. Cushing, T. Wada, F. Sekiguchi, S. Ichida, M. D. Hollenberg, W. K. MacNaughton, et al. Signal Transduction for Proteinase-Activated Receptor-2-Triggered Prostaglandin E2 Formation in Human Lung Epithelial Cells J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 576 - 589. [Abstract] [Full Text] [PDF]

				P. J. Henry, A. D'Aprile, G. Self, T. Hong, and T. S. Mann Inhibitors of Prostaglandin Transport and Metabolism Augment Protease-Activated Receptor-2-Mediated Increases in Prostaglandin E2 Levels and Smooth Muscle Relaxation in Mouse Isolated Trachea J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 995 - 1001. [Abstract] [Full Text] [PDF]