The role of trypsin, trypsin inhibitor, and trypsin receptor in the onset and aggravation of pancreatitis

J Gastroenterol 2006; 41:832836 DOI 10.1007/s00535-006-1874-2

ReviewThe role of trypsin, trypsin inhibitor, and trypsin receptor in the onset and aggravation of pancreatitis

Masahiko Hirota, Masaki Ohmuraya, and Hideo Baba

Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-0811, Japan

serine type 1 (PRSS1) gene, and the onset of pancreatitis was initially reported in 1996.1 That between mutations in the pancreatic secretory trypsin inhibitor (PSTI) gene, which is also known as the serine protease inhibitor Kazal type 1 (SPINK1) gene, and the onset of pancreatitis was reported in 2000.2 Recently, a more detailed understanding of the mechanism of trypsins and PSTIs effects on the onset of pancreatitis has been attained.3 Furthermore, a trypsin receptor of the protease-activated receptor (PAR) family, PAR-2, has been discovered to be present in abundance on the surface of pancreatic acinar and duct cells. In this paper, we introduce a model in which trypsinogen activation (leading to trypsin production), inhibition of trypsin activity by PSTI, and activation of PAR-2 (trypsin receptor) function together to inuence the onset and aggravation of pancreatitis.

Activation of trypsinogen (trypsin production) and inhibition of trypsin activity by PSTI

Pancreatic digestive enzymes are stored as inactivated precursors (i.e., trypsin as trypsinogen) in zymogen granules. Under normal conditions, activation of pancreatic digestive enzymes is strictly controlled (Table 1) to prevent autodigestion of the pancreas, which would develop into pancreatitis. However, in certain circumstances, excessive amounts of pancreatic trypsinogen are activated to trypsin (ectopic activation), activating other downstream zymogens. Trypsinogen and PSTI are synthesized in acinar cells of the pancreas and packed in the same zymogen granule. Pancreatitis can ultimately develop if pancreatic activation of trypsinogen is too high or trypsin binding ability of PSTI is too low (Fig. 1). PSTI is thought to inhibit up to 20% of the potential trypsin activity within the pancreas by binding to its catalytic site. In mice, lack of PSTI activity by knockout of the gene results in the disappearance of the Received: December 11, 2005 / Accepted: July 18, 2006Reprint requests to: H. Baba

Trypsin activity is properly suppressed in the pancreatic acinar cells under normal conditions. A small amount of trypsinogen is converted to active trypsin and inactivated by pancreatic secretory trypsin inhibitor (PSTI), thereby...