Pathologically relevant trypsinogen activation in pancreatitis.

Abstract

Pancreatitis is an inflammatory disorder of the pancreas that occurs in acute, recurrent acute, and chronic forms, often leading to severe complications and long-term functional impairment. The disease develops through multiple pathological mechanisms, including the premature activation of the digestive proenzyme trypsinogen within the pancreas. Conversion of trypsinogen to its active form trypsin may be catalyzed by the lysosomal protease cathepsin B or may occur through autoactivation, a self-amplifying reaction in which trypsin activates trypsinogen. Accumulating evidence from genetic, biochemical, and animal model studies on trypsinogen mutations associated with human pancreatitis strongly supports autoactivation as a key driver of disease pathogenesis, whereas cathepsin B-mediated activation may play a context-dependent, lesser role. This review explores the biochemical pathways of intrapancreatic trypsinogen activation and discusses their respective contributions to the multifactorial pathogenesis of pancreatitis.