Dysregulation of the calpain-calpastatin system plays a role in the development of cerulein-induced acute pancreatitis in the rat

Abstract

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.

Oxidant-impaired intracellular Ca2+ signaling in pancreatic acinar cells: role of the plasma membrane Ca2+-ATPase

“…Moreover, and of direct relevance to the present study, two groups have demonstrated that Ca 2ϩ -dependent activation of calpain leads to activation of the cytokine transcription factor, NF-KB, and pancreatic acinar cell injury (47,51). In addition, cell injury associated with cerulean-induced pancreatitis was markedly ameliorated by calpain inhibitors (47,52). Finally, there is now evidence that H 2 O 2 can directly activate calpain, and that this leads to similar cell injury to that observed during pancreatitis (51).…”

Dominant Role for Calpain in Thromboxane-Induced Neuromicrovascular Endothelial Cytotoxicity

“…5A) (Weber et al, 2004;Park and Ferreira, 2005), whereas -calpain was unaltered. Generation of m-calpain active fragment was inhibited by treatment with PKC and PLC inhibitors calphostin-C and U73122, respectively; correspondingly, U-46619 evoked an increase in inositol phosphate generation, which was blocked by U73122 (Fig.…”

The Potential Effect of Proteasome Inhibitor PS-341 on Severe Acute Pancreatitis Detected by Positron Emission Tomography in ICR Mice

“…Several studies have shown that the activation of NF-kB could be inhibited by blocking the degradation of its inhibitor protein IkBa and thus attenuate the severity of experimental acute pancreatitis [30][31][32][33]. The ubiquitinproteasome pathway is the principle pathway for the degradation of IkBa [34], so inhibition of proteasome mediated IkBa degradation may provide a potential treatment option for severe acute pancreatitis.…”