A New Protease Inhibitor, Nafamostat Mesilate (FUT-175), Protects Pancreatic Acinar Cells in CDE-Diet-lnduced Pancreatitis in Mice

Abstract

This study was designed to evaluate the role of lysosomal enzymes in the pathogenesis of acute pancreatitis and also evaluate the protective effects of a new synthetic protease inhibitor, naf amostat mesilate (FUT-175), against pancreatic injuries in mice with severe acute pancreatitis induced by a cho-line-deficient ethionine-supplemented (CDE) diet. The CDE diet induced a significant redistribution of cathepsin B activity from the lysosomal fraction (about 30% of the total activity) to the zymogen fraction (about 50%) as compared with the control mice (about 50 and 30%, respectively), which indicated a colocalization of lysosomal enzymes with digestive enzymes in the same sub-cellular compartment. The CDE diet also caused a significant activation of trypsinogen in the pancreatic tissue (14 ± 3 U/mg DNA at 24 h and 21 ± 4U/mg DNA at 48 h). However, FUT-175 exerted significant protective effects against pancreatic injuries induced by CDE diet such as hyperamylasemia (15 ± 2 U/ml at 24 h and 10 ± 3 U/ml at 48 h), high mortality rate (17% at 3 days, 30% at 4 days and 43% at 5 days) as compared with only CDE diet mice (29 ± 3 U/ml at 24 h and 22 ± 3 U/ml at 48 h; 43% at 3 days, 57% at 4 days and 70% at 5 days, respectively). FUT-175 also significantly inhibited the redistribution of cathepsin B activity and activation of trypsinogen (7 ± 2 U/mg DNA at 24 h and 9 ± 2 U/mg DNA at 48 h). These results suggest that lysosomal enzyme, particularly cathepsin B, seems to play an important role in the development of severe acute pancreatitis and that protease inhibitors such as FUT-175 may be clinically beneficial in the treatment of acute pancreatitis.