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Received for publication March 15, 2004.
Revised June 14, 2004.
Accepted for publication June 15, 2004.
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. SLIGRL-NH2 and TFLLR-NH2, 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 COX-1, COX-2, 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 (cPLA2), Ca2+-independent PLA2 (iPLA2), 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-LIGRL-NH2, 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-ERK 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.
Key words:
MAP kinase, PAR, airway, knockout mouse, signal transduction, trypsin
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