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Tryptase inhibitor APC 366 prevents hepatic fibrosis by inhibiting collagen synthesis induced by tryptase/protease-activated receptor 2 interactions in hepatic stellate cells.

Abstract
Protease-activated receptor (PAR) 2 is a G-protein-coupled receptor that is activated by mast cell tryptase. PAR-2 activation augments profibrotic pathways through the induction of extracellular matrix proteins. PAR-2 is widely expressed in hepatic stellate cells (HSCs), but the role of tryptase/PAR-2 interaction in liver fibrosis is unclear. We studied the development of bile duct ligation (BDL)-induced hepatic fibrosis in rats treated with mast cell tryptase inhibitor APC 366, and showed that APC 366 reduced hepatic fibrosis scores, collagen content and serum biochemical parameters. Reduced fibrosis was associated with decreased expression of PAR-2 and α-smooth muscle actin (α-SMA). Our findings demonstrate that mast cell tryptase induces PAR-2 activation to augment HSC proliferation and promote hepatic fibrosis in rats. Treatment with tryptase antagonists may be a novel therapeutic approach to prevent fibrosis in patients with chronic liver disease.
AuthorsJing Lu, Baian Chen, Shengli Li, Quan Sun
JournalInternational immunopharmacology (Int Immunopharmacol) Vol. 20 Issue 2 Pg. 352-7 (Jun 2014) ISSN: 1878-1705 [Electronic] Netherlands
PMID24735816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • ACTA2 protein, human
  • Actins
  • Dipeptides
  • N-(1-hydroxy-2-naphthoyl)arginyl-prolinamide
  • Receptor, PAR-2
  • Collagen
  • Tryptases
Topics
  • Actins (genetics, metabolism)
  • Animals
  • Bile Ducts (surgery)
  • Cell Proliferation (drug effects)
  • Cells, Cultured
  • Collagen (blood)
  • Dipeptides (administration & dosage, pharmacology)
  • End Stage Liver Disease (complications, drug therapy)
  • Fibrosis (etiology, prevention & control)
  • Gene Expression Regulation (drug effects)
  • Hepatic Stellate Cells (drug effects, pathology)
  • Liver Cirrhosis, Experimental (complications, drug therapy)
  • Male
  • Protein Binding (drug effects)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, PAR-2 (genetics, metabolism)
  • Tryptases (antagonists & inhibitors)

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