Influence of chloroquine on diet-induced pancreatitis.
Recent investigations have suggested that digestive zymogens may become activated within the acinar cell during acute pancreatitis. While the molecular events responsible for intracellular zymogen activation remain unknown, several potential enzymatic pathways require an acidic pH to optimally proceed. We therefore proposed that manipulation of subcellular pH might alter the course of experimental pancreatitis. Chloroquine, a weak base that raises the pH of acidic subcellular compartments, was administered to young female mice in which pancreatitis was induced by a choline-deficient, ethionine-supplemented (CDE) diet. Control animals were maintained on regular laboratory chow. Examination of isolated pancreatic acini using acridine orange cytofluorescence demonstrated expansion of acidic subcellular compartments in animals fed the CDE diet. These compartments were effectively neutralized in animals receiving chloroquine. Animals receiving continuous infusions of high-dose chloroquine demonstrated a significant (p < 0.05) decrease in free pancreatic tryptic activity as well as improved survival. These changes were also associated with decreased trypsinogen content in animals treated with high-dose chloroquine, suggesting an additional potential effect of chloroquine on zymogen synthesis and accumulation. One explanation of these findings is that a low-pH compartment may be important in the pathogenesis of diet-induced pancreatitis.
Leach
S D
SD
Department of Surgery, West Haven VA Medical Center, Connecticut.
Bilchik
A J
AJ
Karapetian
O
O
Gorelick
F S
FS
Modlin
I M
IM
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D002738:Chloroquine / Q000494:pharmacology*; D002794:Choline / Q000008:administration & dosage; D004032:Diet / Q000009:adverse effects; D005001:Ethionine / Q000008:administration & dosage; D005260:Female; D006863:Hydrogen-Ion Concentration; D051379:Mice; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D002738:Chloroquine; D000681:Amylases; D014357:Trypsin; D002794:Choline; D005001:Ethionine