Expression and function of proteinase-activated receptor 2 in human bronchial smooth muscle

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