Early events in acute pancreatitis

Pancreatitis is an inflammatory disorder of the exocrine pancreas caused, in most cases, by immoderate alcohol consumption or the passage of gallstones. It was proposed long ago that pancreatitis is essentially a disease in which a premature activation of pancreatic zymogens occurs, which then may lead to an autodigestion of the organ. Recent studies involving animal and isolated cell models have elucidated many of the pathophysiological, cellular, and molecular processes involved in the initial time course of acute pancreatitis. These studies have revealed that pancreatitis begins within the acinar cell and that trypsin and other digestive enzymes play a pivotal role in the disease process. This article addresses the role of cathepsin B and trypsin in the autodigestive cascade that leads to acinar cell injury. It also focuses on the alterations in intracellular Ca++ signaling that precede zymogen activation. Although there is an accumulation of knowledge concerning the enzymatic properties of trypsin from studies using recombinant trypsinogen, into which hereditary pancreatitis-causing mutations were introduced, the specific role and the factors that are involved in activation, inhibition, and degradation of this enzyme, especially the human isoenzymes, remain a matter of intensive research and controversial debate.