Calpain, a
calcium-dependent cytosolic
cysteine protease, is implicated in a multitude of cellular functions but also plays a role in cell death. Recently, we have shown that two ubiquitous
isoforms, termed micro-
calpain and
m-calpain, are expressed in rat pancreatic acinar cells and that
calcium ionophore-induced
calpain activation leads to acinar cell injury. On the basis of these observations, we have now investigated the role of both
calpain forms and the endogenous
calpain inhibitor calpastatin in
acute pancreatitis.
After treatment of rats either without or with
calpain inhibitor Z-Val-Phe methyl ester (ZVP; 60 mg/kg i.p.),
pancreatitis was induced by
cerulein injections (10 microg/kg i.p.; 5 times at hourly intervals).
Calpain activation and
calpastatin expression in the pancreatic tissue were studied by Western blot analysis. Pancreatic injury was assessed by plasma
amylase activity, pancreatic wet/dry weight ratio (
edema), histological and electron-microscopic analyses, as well as fluorescence labeling of actin filaments.
Cerulein caused an activation of both micro-
calpain and
m-calpain, accompanied by degradation of
calpastatin. Prophylactic administration of ZVP reduced the
cerulein-induced
calpain activation but had no effect on
calpastatin alterations. In correlation to the diminished
calpain activity, the severity of
pancreatitis decreased as indicated by a decline in
amylase activity (P < 0.01), pancreatic
edema formation (P < 0.05), histological score for eight parameters (P < 0.01), and actin filament alterations. Our findings support the hypothesis that dysregulation of the
calpain-
calpastatin system may play a role in the onset of
acute pancreatitis.