Mechanisms of intracellular zymogen activation

The pancreatic acinar cell is potentially the initial site of injury that b egins the series of events leading to acute pancreatitis, pathological intr apancreatic zymogen activation occurs in experimental pancreatitis in anima ls and in human pancreatitis. Intracellular activation has been clearly lin ked to aberrant zymogen processing in one form of hereditary pancreatitis; in this genetic disease a mutation in cationic trypsinogen may eliminate th e degradation of any trypsin activated in the acinar cell. Recent studies h ave also provided the first direct evidence that trypsinogen activation tak es place early in the course of caerulein-induced pancreatitis; parallel st udies have used isolated pancreatic acini and conditions that simulate thos e that cause pancreatitis in vivo to demonstrate that zymogens can be patho logically activated in isolated cells. A unique acinar cell pathway regulat es the intracellular proteinase processing of zymogens to their active form s. Stimulating the acinar cell with supramaximal concentrations of cholecys tokinin (CCK) or carbamylcholine can activate this pathway. The activation depends on a low pH compartment within the acinar cell and activation of an intracellular serine protease. A marker of trypsinogen processing, the try psinogen activation peptide (TAP), is generated in acinar cell compartments that do not overlap with secretory granules. This compartment overlaps wit h a marker of recycling endosomes and lysosomes. Thus, zymogen processing w ithin the acinar cell proceeds in a distinct subcellular compartment and is dependent on a low pH environment and activation of serine proteases.