SUBCELLULAR KINETICS OF EARLY TRYPSINOGEN ACTIVATION IN ACUTE RODENT PANCREATITIS

To investigate the debated role of intracellular trypsinogen activatio n and its relation to lysosomal enzyme redistribution in the pathogene sis of acute pancreatitis, rats were infused with the cholecystokinin analog caerulein at 5 mu g . kg(-1) . h(-1) for intervals up to 3 h, a nd the changes were contrasted with those in animals receiving saline or 0.25 mu g . kg(-1) . h(-1) caerulein. Saline or 0.25 mu g . kg(-1) . h(-1) caerulein did not induce significant changes. In contrast, 5 m u g . kg(-1) . h(-1) caerulein caused significant hyperamylasemia and pancreatic edema within 30 min. Pancreatic content of trypsinogen acti vation peptide (TAP) increased continuously (significant within 15 min ). TAP generation was predominantly located in the zymogen fraction du ring the first hour but expanded to other intracellular compartments t hereafter. Cathepsin B activity in the zymogen compartment increased c ontinuously throughout the experiments and correlated significantly wi th TAP generation in the same compartment. Total trypsinogen content i ncreased to 143% with marked interstitial trypsinogen accumulation aft er 3 h. Supramaximal caerulein stimulation causes trypsinogen activati on by 15 min that originates in the zymogen compartment and is associa ted with increasing cathepsin B activity in this subcellular compartme nt. However, a much larger pool of trypsinogen survives and accumulate s in the extracellular space and may become critical in the evolution of necrotizing pancreatitis.