Abstract
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.
Footnotes
-
This work was supported in part by a grant-in-aid for Scientific Research from the Japan Society of the Promotion of Science.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.104.068387.
-
ABBREVIATIONS: PAR, proteinase-activated receptor; AACOCF3, arachidonyl trifluoromethyl ketone; BEL, bromoenol lactone; COX, cyclooxygenase; cPLA2, cytosolic Ca2+-dependent phospholipase A2; 2f-LIGRL-NH2, 2-furoyl-Leu-Ile-Gly-Arg-Leu-amide; iPLA2, Ca2+-independent phospholipase A2; SLIGRL-NH2, Ser-Leu-Ile-Gly-Arg-Leu-amide; TFLLR-NH2, Thr-Phe-Leu-Leu-Arg-amide; MEK, mitogen-activated protein kinase kinase; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; SC-560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole; NS-398, N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide; PD98059, 2-(2′-amino-3′-methoxyphenyl)-oxanaphthalen-4-one; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5(4-pyridyl) imidazole; GF109203X, 3-(1-(3-(dimethylamino)propyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride; RHC-80267, 1,6-di(O-(carbamoyl)cyclohexanone oxime)hexane.
- Received March 12, 2004.
- Accepted June 15, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|