IS AN ELEVATED CONCENTRATION OF ACINAR CYTOSOLIC-FREE IONIZED CALCIUMTHE TRIGGER FOR ACUTE-PANCREATITIS

The pathogenesis of acute pancreatitis is poorly understood, despite w ell-recognised precipitating factors. Current evidence suggests that t he earliest abnormalities of acute pancreatitis arise within acinar ce lls, but the key intracellular trigger has yet to be identified. Withi n the pancreas, physiological concentrations of secretagogues bind to G-protein-linked cell-surface receptors on acinar cells, evoking short , oscillatory spikes of acinar cytosolic-free ionised calcium ([Ca2+]( i)), an ubiquitous intracellular messenger. Specific effects within ac inar cells include initiation of enzyme release through the phosphoryl ation cascades of stimulus-secretion coupling. Low resting levels of [ Ca2+](i) are restored by Ca2+-ATPase, which pumps calcium into the end oplasmic reticulum and out of the cell. If high concentrations of [Ca2 +](i) persist, toxicity results, intracellular signalling is disrupted , and cell damage occurs. Sustained elevations in acinar [Ca2+](i) res ult from exposure to high concentrations of secretagogues, high doses of which also induce acute pancreatitis. Similarly, sustained elevatio ns of [Ca2+](i) may result from ductal hypertension, alcohol, hypoxia, hypercalcaemia, hyperlipidaemia, viral infection, and various drugs-a ll factors known to precipitate acute pancreatitis. We suggest that th ese factors precipitate acute pancreatitis by causing either excessive release of acinar [Ca2+](i), or damage to the integrity of mechanisms that restore low resting levels of [Ca2+](i), and that the consequent calcium toxicity is the key trigger in the pathogenesis of acute panc reatitis.