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Laboratoire de Physiologie Cellulaire Respiratoire, Inserm E9937, Université Bordeaux 2, 33076 Bordeaux, France
Tryptase, the major mast cell product, is considered to play an important role in airway inflammation and hyperresponsiveness. Tryptase produces different, sometimes opposite, effects on airway responsiveness (bronchoprotection and/or airway contraction). This study was designed to examine the effect of human lung tryptase and activation of protease-activated receptor (PAR)-2 by synthetic activated peptide (AP) SLIGKV-NH2 on Ca2+ signaling in human airway smooth muscle (HASM) cells. Immunocytochemistry revealed that PAR-2 was expressed by HASM cells. Tryptase (7.5-30 mU/ml) induced a concentration-dependent transient relative rise in cytoplasmic Ca2+ concentration ([Ca2+]i) that reached 207 ± 32 nM (n = 10) measured by indo 1 spectrofluorometry. The protease inhibitors leupeptin or benzamidine (100 µM) abolished tryptase-induced [Ca2+]i increase. Activation of PAR-2 by AP (1-100 µM) also induced a concentration-dependent transient rise in [Ca2+]i, whereas the reverse peptide produced no effect. There was a homologous desensitization of the [Ca2+]i response on repeated stimulation with tryptase or AP. U-73122, a specific phospholipase C (PLC) antagonist, xestospongin, an inositol trisphosphate (IP3)-receptor antagonist, or thapsigargin, a sarcoplamic Ca2+-ATPase inhibitor, abolished tryptase-induced [Ca2+]i response, whereas Ca2+ removal, in the additional presence of EGTA, had no effect. Calphostin C, a protein kinase C inhibitor, increased PAR-2 [Ca2+]i response. Our results indicate that tryptase activates a [Ca2+]i response, which appears as PAR-2 mediated in HASM cells. Signal transduction implicates the intracellular Ca2+ store via PLC activation and thus via the IP3 pathway. This study provides evidence that tryptase, which is increasingly recognized as an important mediator in airway inflammation and hyperresponsiveness, is also a potent direct agonist at the site of airway smooth muscle.
calcium release; protease; protease-activated receptors; cytoplasmic calcium concentration cell culture
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