Physiology and pathophysiology of proteinase-activated receptors (PARs): Role of tryptase/PAR-2 in vascular endothelial barrier function

Yoshinori Itoh, Toshiaki Sendo, Ryozo Oishi

Research output: Contribution to journalShort survey

33 Citations (Scopus)

Abstract

Proteinase-activated receptor-2 (PAR-2) plays important roles in a variety of pathophysiological functions, including inflammatory responses and nociception. In this minireview, we describe the role of PAR-2 in acute inflammatory responses in lungs associated with iodinated radiographic contrast medium (RCM). Intravenous injection of RCM to rats induces lung injury characterized by vascular hyperpermeability, edema, and respiratory depression. Nafamostat, which is found to be the most potent and specific tryptase inhibitor, prevents RCM-induced lung injury. In cultured endothelial cells of human pulmonary artery and bovine aorta, RCM, when applied in combination with mast cells, disrupts barrier function evaluated by the permeability of Evans blue through a monolayer of cultured cells, which is blocked by nafamostat and mimicked by tryptase and PAR-2-activating peptide. The tryptase-induced barrier dysfunction is blocked completely by a phospholipase C inhibitor and partially inhibited by a IP3 receptor blocker, protein kinase C inhibitor, or Rho kinase inhibitor. Morphological observations reveal the formation of actin stress fibers and disappearance of the intercellular meshwork structure of vascular endothelial-cadherin after application of RCM or PAR-2 ligands. Therefore, the release of mast cell tryptase and subsequent activation of endothelial PAR-2 are involved in acute lung injury induced by RCM.

Original languageEnglish
Pages (from-to)14-19
Number of pages6
JournalJournal of Pharmacological Sciences
Volume97
Issue number1
DOIs
Publication statusPublished - Jan 1 2005
Externally publishedYes

Keywords

  • Mast cell tryptase
  • Nafamostat
  • Proteinase-activated receptor-2
  • Radiographic contrast medium
  • Vascular permeability

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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