The role of calcium in pancreatitis.

BACKGROUND/AIMS: A large, sustained increase in acinar [Ca 2+ ] i may play a key role in the pathogenesis of acute pancreatitis. Many mechanisms which lead to cell damage in vitro and pancreatitis in vivo, such as free radicals or supraphysiological cerulein concentrations, cause a rapid increase in [Ca 2+ ] i in pancreatic acinar cells. Little is known about why [Ca 2+ ] i increases in some instances stimulate secretion and in other instances initiate cell death. So far, [Ca 2+ ] i increases were thought to represent physiological signals when they occurred as oscillations at the single cell level. METHODOLOGY: This paper reviews recent literature and our own original research about the role of calcium in the function of pancreatic acinar cells and the development of pancreatitis. RESULTS: Recent studies showed that exposure of acinar cells to free radicals not only caused a bulk increase in [Ca 2+ ] i but also resulted in calcium oscillations which had a lower frequency than, but similar amplitude to oscillations occurring after physiological stimuli. The absolute increase in [Ca 2+ ] i did not definitely determine the cellular response. Instead, the duration of [Ca 2+ ] i increase may have been more important. In contrast to previous belief of a direct relationship between [Ca 2+ ] i oscillations and exocytosis, recent results show that radicals can induce [Ca 2+ ] i oscillations which do not exert exocytosis but inhibit the secretory response to physiological stimuli. Further experiments showed that the [Ca 2+ ] i release caused by radicals originates from thapsigargin-insensitive, ryanodine-sensitive stores. CONCLUSIONS: The origin and duration of [Ca 2+ ] i increases rather than their extent or oscillatory nature, determine whether the cell will secrete or die. An abnormal [Ca 2+ ] i increase can trigger trypsin activation, acinar cell damage and acute pancreatitis. This hypothesis is supported by studies which show that calcium chelators inhibit radical-induced trypsin activation as well as cell necrosis and apoptosis. Thus, an inhibition of pathological [Ca 2+ ] i release may have a therapeutic potential.