Clinical meaning
Under normal conditions, pancreatic acinar cells synthesize and store digestive enzymes as inactive zymogens (trypsinogen, chymotrypsinogen, proelastase, prophospholipase A2) within zymogen granules, with protective mechanisms including pancreatic secretory trypsin inhibitor (PSTI/SPINK1) and compartmentalization preventing premature activation. In pancreatitis, an inciting event (gallstone impaction, alcohol toxicity, or genetic PRSS1 mutation) disrupts intracellular calcium homeostasis and causes lysosomal hydrolase cathepsin B to colocalize with zymogen granules, prematurely converting trypsinogen to trypsin within the acinar cell. Trypsin then activates the entire enzyme cascade: elastase digests blood vessel walls causing hemorrhage, phospholipase A2 destroys cell membranes causing fat necrosis and generating toxic lysophospholipids, and kallikrein activates the kinin system causing vasodilation, increased vascular permeability, and edema. This local autodigestion triggers release of DAMPs and cytokines (TNF-α, IL-1β, IL-6) that recruit neutrophils and macrophages, potentially escalating to SIRS, multi-organ dysfunction, and death.