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, Pierangelo Geppetti

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1672-1680
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume161
Issue number5
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Ricciardolo, F. L. M., Steinhoff, M., Amadesi, S., Guerrini, R., Tognetto, M., Trevisani, M., Creminon, C., Bertrand, C., Bunnett, N. W., Fabbri, L. M., Salvadori, S., & Geppetti, P. (2000). Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways. American Journal of Respiratory and Critical Care Medicine, 161(5), 1672-1680. https://doi.org/10.1164/ajrccm.161.5.9907133