Protease Activation and Inflammation in Acute Pancreatitis

Abstract: Approximately 10—20 % of patients with acute pancreatitis (AP) develop a severe disease with high mortality and morbidity. Activation of pancreatic proteases, the inflammatory response and impaired pancreatic circulation are pathophysiological events that are important in order for the disease to develop. There is no specific treatment for severe AP, and no useful marker for predicting the severity of the disease upon admission to the hospital. In this thesis, markers of early pathophysiological events in AP are investigated, with emphasis on protease activation and inflammation. ProCarboxypeptidase B (proCAP) is a pancreatic proenzyme which, particularly in severe AP, is activated by trypsin thereby forming Carboxypeptidase B (aCAP ) and the activation peptide of proCarboxypeptidase B (CAPAP). An ELISA method for measurement of serum aCAP in patients with AP was developed, and aCAP was shown to inhibit fibrinolysis in vitro. This may contribute to formation of necrosis in AP. The prediction of severity and pathophysiology was studied in patients with mild (n=124) and severe (n=16) AP. Markers of protease activation (aCAP, CAPAP) and inflammation (Monocyte Chemoattractant protein-1 (MCP-1) and CRP) were found to be elevated within 24 hours in patients with severe AP. Protease activation decreased after 48 hours, yet inflammation persisted for a longer period of time. Markers of pancreatic leakage (proCAP) decreased with time without differences in patients with mild and severe AP. MCP-1 exhibited a good capacity at predicting severe AP upon hospital admission. CAPAP and aCAP may also be useful in predicting the degree of severity.