title: 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.
authors.affiliation: Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing 100069, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing 100069, China.
authors.forename: Baian
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing 100069, China.
authors.forename: Shengli
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing 100069, China. Electronic address: sunquan@ccmu.edu.cn.
authors.forename: Quan
authors.initials: Q
authors.lastname: Sun
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000097:blood; D004151:Dipeptides / Q000008:administration & dosage* / Q000494:pharmacology; D058625:End Stage Liver Disease / Q000150:complications / Q000188:drug therapy*; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000188:drug therapy*; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism; D053802:Tryptases / Q000037:antagonists & inhibitors
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D004151:Dipeptides; C094700:N-(1-hydroxy-2-naphthoyl)arginyl-prolinamide; D044464:Receptor, PAR-2; D003094:Collagen; D053802:Tryptases
keywords: Bile duct ligation; Hepatic fibrosis; Protease-activated receptor 2; Tryptase