The effect of chloroquine administration on two experimental models of acute pancreatitis.
BACKGROUND
Recent experimental findings have suggested that activation of trypsinogen by cathepsin B within acidic pancreatic acinar cell cytoplasmic vacuoles may be a critical early event in both secretagogue and diet-induced pancreatitis. The weak base chloroquine accumulates within acidic intracellular compartments, raises their pH, and can inhibit proteolysis as well as cathepsin B.


METHODS
We have investigated the effect of in vivo chloroquine administration on both secretagogue and diet-induced experimental pancreatitis to determine if raising the pH of cytoplasmic vacuoles in these models of pancreatitis would have a protective effect.


RESULTS
Infusion of chloroquine (5 mg.kg-1.h-1) resulted in the uptake and concentration of chloroquine in the pancreas, an increase in the pH of acinar cell acidic compartments, and interference with the pH-dependent sorting of lysosomal hydrolases from digestive enzyme zymogens. However, chloroquine administration did not have a protective effect against the hyperamylasemia, the pancreatic edema, the morphological changes or the mortality that is associated with these models of pancreatitis.


CONCLUSIONS
These observations lead us to conclude that raising the pH of acinar cell acidic compartments by in vivo administration of chloroquine does not prevent either secretagogue or diet-induced pancreatitis.
Department of Surgery, Beth Israel Hospital, Boston, Massachusetts.
M M
MM
Lerch
A K
AK
Saluja
R
R
Dawra
M
M
Saluja
M L
ML
Steer
D000208:Acute Disease; D000818:Animals; D002401:Cathepsin B / Q000494:pharmacology; D002738:Chloroquine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004789:Enzyme Activation; D006863:Hydrogen-Ion Concentration; D008297:Male; D010195:Pancreatitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D014362:Trypsinogen / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
D002738:Chloroquine; D014362:Trypsinogen; D002401:Cathepsin B