Local and Systemic Zymogen Activation in Human Acute Pancreatitis

Abstract

Background: Activation of trypsinogen and phospholipase A₂ is an early event in pancreatic inflammation, but little is known about zymogen activation and the severity of human pancreatitis. Methods: Using a new fluoroimmunoassay we measured trypsinogen activation peptide (TAP) and phospholipase A₂ activation peptide (PROP) in plasma and ascites in 25 patients with acute pancreatitis. TAP, PROP, Pro-PROP and pancreatic PLA₂-I were measured in plasma for 14 days and in pancreatic necroses, ascitic fluid and pleural effusions. Results: All 16 patients with severe acute pancreatitis (SAP) had pancreatic necrosis, 10 developed systemic complications like sepsis, pulmonary or renal failure, 6 had infected necrosis, and 4 died. All 9 patients with mild pancreatitis (MAP) survived. Plasma TAP on admission was higher in patients with SAP than in those with MAP and increased in infected necroses. It did not correlate with systemic complications. Systemic PROP was not increased in complicated courses but was significantly higher in patients with MAP than in those with SAP on admission. Pro-PROP was higher in patients with SAP than in those with MAP but was not correlated with systemic complications. Plasma pancreatic PLA₂-I was increased but not different in patients with SAP and those with MAP. In patients with pancreatic necrosis, TAP and PROP were highest, while in those with post-acute pancreatic abscess, only PROP and Pro-PROP were high. In patients with pleural effusion, TAP was low and PROP/ Pro-PROP were high. Conclusion: Trypsinogen and PLA₂-I activation are early events in acute pancreatitis and the activation peptides can be detected in plasma. In the pancreas, trypsinogen activation is accompanied by PLA₂-I activation in patients with pancreatic necrosis. However, in our study, organ complications in SAP patients was not associated with increased plasma PROP.

Severe acute pancreatitis is related to increased early urinary levels of the activation peptide of pancreatic phospholipase A2

“…This ratio returned to normal 25-36 h after symptom onset and then rose steadily to similar peak levels over the next 96 h. Comparison with the present study is not possible, because the actual urinary PROP values were not given [12]. Another small clinical study reported that the plasma PROP levels were actually lower in severe as compared with mild acute pancreatitis [13].…”

“…Since there have only been two small previous studies of PROP in patients with acute pancreatitis with apparently conflicting results [12,13], we report the findings of a large prospective multicentre study.…”

Structural Insight into the Activation Mechanism of Human Pancreatic Prophospholipase A2

“…It is activated by trypsin in the duodenum. The activation of pro-hG1B by cleavage of the PROP, a heptapeptide of the sequence DSGISPR, is linked to diseases like pancreatitis (8) and acute lung injury (9). Circulating hG1B, mostly in the form of pro-hG1B, indicates pancreatic injury in acute pancreatitis (10).…”

Prophylactic Glycine Administration Attenuates Pancreatic Damage and Inflammation in Experimental Acute Pancreatitis

“…During acute pancreatitis, the conversion of trypsinogen into active trypsin within acinar cells is followed by an activation of several enzymes, such as elastase, phospholipase A 2 and NADPH oxidase [38]. Through the increase of intracellular calcium concentration, elastase and ROS (H 2 O 2 ), NADPH oxidase and phospholipase A 2 are activated [39,40]. Here, it should be considered that glycine inhibits phospholipase A 2 , an event which leads to stabilization of the cell membrane [41].…”