The pancreas misled: signals to pancreatitis.

Acute pancreatitis is an increasingly common and sometimes severe disease for which there is little specific therapy. Chronic pancreatitis is a common and grossly debilitating sequel that is largely irreversible, whatever treatment is adopted. In the face of these burdens, the absence of specific treatments is a spur to research. The acinar cell is the primary target of injury from alcohol metabolites, bile, hyperlipidaemia, hyperstimulation and other causes. These induce abnormal, prolonged, global, cytosolic calcium signals, the prevention of which also prevents premature digestive enzyme activation, cytokine expression, vacuole formation and acinar cell necrosis. Such agents increase calcium entry through the plasma membrane and/or increase calcium release from intracellular stores, shown to result from effects on calcium channels and calcium pumps, or their energy supply. A multitude of signalling mechanisms are activated, diverted or disrupted, including secretory mechanisms, lysosomal regulators, inflammatory mediators, cell survival and cell death pathways, together with or separately from calcium. While recent discoveries have increased insight and suggest prophylaxis or treatment targets, more work is required to define the mechanisms and interactions of cell signalling pathways in the pathogenesis of pancreatitis.