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Am. J. Respir. Crit. Care Med., Volume 161, Number 5, May 2000, 1672-1680

Presence and Bronchomotor Activity of Protease-Activated Receptor-2 in Guinea Pig Airways

FABIO L. M. RICCIARDOLO, MARTIN STEINHOFF, SILVIA AMADESI, REMO GUERRINI, MICHELE TOGNETTO, MARCELLO TREVISANI, CHRISTOPHE CREMINON, CLAUDE BERTRAND, NIGEL W. BUNNETT, LEONARDO M. FABBRI, SEVERO SALVADORI, and PIERANGELO GEPPETTI

Departments of Experimental and Clinical Medicine and Pharmaceutical Chemistry, University of Ferrara, Ferrara, Italy; CEA, SPI/DRM, CEA-Saclay, Gif-sur-Yvette, France; Departments of Physiology and Surgery, University of California, San Francisco; and Inflammatory Diseases Unit, Roche Bioscience, Palo Alto, California

The protease activated receptor-2 (PAR-2) belongs to a family of G-protein-coupled receptors that are activated by proteolysis. Trypsin cleaves PAR-2, exposing an N-terminal tethered ligand (SLIGRL) that activates the receptor. Messenger RNA (mRNA) for PAR-2 was found in guinea pig airway tissue by reverse transcription-polymerase chain reaction, and PAR-2 was found by immunohistochemistry in airway epithelial and smooth-muscle cells. In anesthetized guinea pigs, trypsin and SLIGRL-NH2 (given intratracheally or intravenously) caused a bronchoconstriction that was inhibited by the combination of tachykinin-NK1 and -NK2 receptor antagonists and was potentiated by inhibition of nitric oxide synthase (NOS). Trypsin and SLIGRL-NH2 relaxed isolated trachea and main bronchi, and contracted intrapulmonary bronchi. Relaxation of main bronchi was abolished or reversed to contraction by removal of epithelium, administration of indomethacin, and NOS inhibition. PAR-1, PAR-3, and PAR-4 were not involved in the bronchomotor action of either trypsin or SLIGRL-NH2, because ligands of these receptors were inactive either in vitro or in vivo, and because thrombin (a PAR-1 and PAR-3 agonist) did not show cross-desensitization with PAR-2 agonists in vivo. Thus, we have localized PAR-2 to the guinea-pig airways, and have shown that activation of PAR-2 causes multiple motor effects in these airways, including in vivo bronchoconstriction, which is in part mediated by a neural mechanism.




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