Pancreatic injuries in rats with fecal peritonitis: protective effect of a new synthetic protease inhibitor, sepinostat mesilate (FUT-187).

To evaluate the effects of sepsis on the exocrine pancreas, we studied (1) serum amylase levels, pancreatic water and trypsin content; (2) pancreatic histological changes; (3) pancreatic subcellular distribution of lysosomal enzyme in the acinar cells; and (4) protective effects of a new synthetic protease inhibitor, FUT-187 against the pancreatic injuries in sepsis of rats induced by cecal ligation and puncture. Elevated serum amylase levels, increased pancreatic water and trypsin content, were observed in rats with fecal peritonitis induced by cecal ligation and puncture. Subcellular redistribution of lysosomal enzyme, cathepsin B, activity from the lysosomal fraction to the zymogen fraction was also observed. FUT-187 was found to significantly prevent these pancreatic injuries induced by fecal peritonitis. These results indicate that the exocrine pancreas is injured during sepsis, and that some unknown protease activities, which are present during sepsis and are susceptible to the inhibition of FUT-187, seem to play an important role in the pathogenesis of the pancreatic injuries induced by fecal peritonitis. These results also indicate the important pathological role of lysosomal enzymes in the pancreatic injuries induced by sepsis.