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Am. J. Respir. Crit. Care Med., Volume 164, Number 7, October 2001, 1276-1281

Expression and Function of Proteinase-activated Receptor 2 in Human Bronchial Smooth Muscle

FABIEN SCHMIDLIN, SILVIA AMADESI, REYNAL VIDIL, MARCELLO TREVISANI, NADINE MARTINET, GEORGE CAUGHEY, MICHELE TOGNETTO, GIORGIO CAVALLESCO, CRISTINA MAPP, PIERANGELO GEPPETTI, and NIGEL W. BUNNETT

Departments of Surgery and Physiology, and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; Clerc Poumon, Faculté de Médecine de Nancy, Nancy, France; and Department of Experimental and Clinical Medicine and Surgery, University of Ferrara, Ferrara, Italy

Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 (PAR2) to induce alterations in contraction of airway smooth muscle that have been implicated in asthma in experimental animals. Although tryptase inhibitors are under development for treatment of asthma, little is known about the localization and function of PAR2 in human airways. We detected PAR2 expression in primary cultures of human airway smooth muscle cells using reverse transcriptase/polymerase chain reaction (RT-PCR) and immunofluorescence. The PAR2 agonists trypsin, tryptase, and an activating peptide (SLIGKV-NH2) stimulated calcium mobilization in these cells. PAR2 agonists strongly desensitized responses to a second challenge of trypsin and SLIGKV-NH2, but not to thrombin, indicating that they activate a receptor distinct from the thrombin receptors. Immunoreactive PAR2 was detected in smooth muscle, epithelium, glands, and endothelium of human bronchi. Trypsin, SLIGKV-NH2, and tryptase stimulated contraction of isolated human bronchi. Contraction was increased by removal of the epithelium and diminished by indomethacin. Thus, PAR2 is expressed by human bronchial smooth muscle where its activation mobilizes intracellular Ca2+ and induces contraction. These results are consistent with the hypothesis that PAR2 agonists, including tryptase, induce bronchoconstriction of human airway by stimulating smooth muscle contraction. PAR2 antagonists may be useful drugs to prevent bronchoconstriction.




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