Esterase inhibitors prevent lysosomal enzyme redistribution in two noninvasive models of experimental pancreatitis.
Earlier studies have indicated that lysosomal enzymes such as cathepsin B become redistributed within pancreatic acinar cells during the early stages of both diet- and secretagogue-induced acute pancreatitis. As a result, cathepsin B and digestive zymogens became colocalized within large cytoplasmic vacuoles. As cathepsin B can activate trypsinogen, this colocalization could result in intracellular digestive enzyme activation. The present study investigates the protective effects of gabexate mesilate (FOY) and camostate (FOY 305) on both of these noninvasive models of experimental pancreatitis. These esterase inhibitors prevented the hyperamylasemia, pancreatic edema, and acinar cell vacuolization that characterize secretagogue-induced pancreatitis and the hyperamylasemia and mortality that characterize diet-induced pancreatitis. In addition, FOY and FOY 305 were found to significantly decrease the subcellular redistribution of cathepsin B that occurs in both models. These findings indicate that enzyme activity sensitive to inhibition by FOY and FOY 305 may be critical to the redistribution phenomenon that characterizes both of these models of pancreatitis.
Ohshio
G
G
Department of Surgery, Harvard Digestive Diseases Center, Beth Israel Hospital, Boston, Massachusetts.
Saluja
A K
AK
Leli
U
U
Sengupta
A
A
Steer
M L
ML
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D004952:Esters; D016670:Gabexate; D006146:Guanidines / Q000627:therapeutic use*; D008297:Male; D010179:Pancreas / Q000201:enzymology; D010195:Pancreatitis / Q000188:drug therapy* / Q000201:enzymology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D014617:Vacuoles / Q000187:drug effects
D004952:Esters; D006146:Guanidines; D011480:Protease Inhibitors; C034532:camostat; D016670:Gabexate; D000681:Amylases; D002401:Cathepsin B