OBJECTIVES: The pathophysiology of acute pancreatitis is strongly associated with autoactivation of trypsin. The biologic activity of trypsin on cells is attributed to the activation of protease-activated receptor-2 (PAR-2). We hypothesize that trypsin may activate acinar cells or inflammatory cells through PAR-2 signals in acute pancreatitis. METHODS: We immunochemically analyzed the expression of PAR-2 in the rat acinar cell line, ARIP, and the rat pancreas, using anti-rat PAR-2 cleavage site (PCS) and anti-rat PAR-2 N-terminal fragment (PNF) antibodies. Plasma levels of PNF were determined. Furthermore, the effects of the anti-rat PCS antibody and nafamostat mesylate, a potent trypsin inhibitor, on PAR-2 activation during acute pancreatitis were also analyzed. RESULTS: ARIP cells expressed PAR-2, which was activated by exogenous trypsin activity. We also showed that PAR-2 is strongly expressed in pancreatic acinar and duct cells and that it is activated in rat cerulein-induced acute pancreatitis. The anti-rat PCS antibody and nafamostat mesylate reduced interleukin-6 and interferon gamma production and alleviated distant organ injury. CONCLUSIONS: These results suggest that trypsin and its specific receptor, PAR-2, play an important role in cytokine production and the resultant development of distant organ injury during rat acute pancreatitis.
OBJECTIVES: The pathophysiology of acute pancreatitis is strongly associated with autoactivation of trypsin. The biologic activity of trypsin on cells is attributed to the activation of protease-activated receptor-2 (PAR-2). We hypothesize that trypsin may activate acinar cells or inflammatory cells through PAR-2 signals in acute pancreatitis. METHODS: We immunochemically analyzed the expression of PAR-2 in the rat acinar cell line, ARIP, and the rat pancreas, using anti-ratPAR-2 cleavage site (PCS) and anti-ratPAR-2 N-terminal fragment (PNF) antibodies. Plasma levels of PNF were determined. Furthermore, the effects of the anti-rat PCS antibody and nafamostat mesylate, a potent trypsin inhibitor, on PAR-2 activation during acute pancreatitis were also analyzed. RESULTS: ARIP cells expressed PAR-2, which was activated by exogenous trypsin activity. We also showed that PAR-2 is strongly expressed in pancreatic acinar and duct cells and that it is activated in rat cerulein-induced acute pancreatitis. The anti-rat PCS antibody and nafamostat mesylate reduced interleukin-6 and interferon gamma production and alleviated distant organ injury. CONCLUSIONS: These results suggest that trypsin and its specific receptor, PAR-2, play an important role in cytokine production and the resultant development of distant organ injury during ratacute pancreatitis.
Authors: Eugene P Ceppa; Victoria Lyo; Eileen F Grady; Wolfgang Knecht; Sarah Grahn; Anders Peterson; Nigel W Bunnett; Kimberly S Kirkwood; Fiore Cattaruzza Journal: Am J Physiol Gastrointest Liver Physiol Date: 2011-03-24 Impact factor: 4.052
Authors: Ron Piran; Seung-Hee Lee; Pia Kuss; Ergeng Hao; Robbin Newlin; José Luis Millán; Fred Levine Journal: Cell Death Dis Date: 2016-11-03 Impact factor: 8.469