Transgenic expression of pancreatic secretory trypsin inhibitor-I ameliorates secretagogue-induced pancreatitis in mice

JD Nathan, J Romac, RY Peng, M Peyton… - Gastroenterology, 2005 - Elsevier
JD Nathan, J Romac, RY Peng, M Peyton, RJ MacDonald, RA Liddle
Gastroenterology, 2005Elsevier
Background & aims Endogenous trypsin inhibitors are believed to inhibit protease activity if
trypsin becomes inadvertently activated within the acinar cell. However, this action remains
unproven, and the role of endogenous pancreatic trypsin inhibitors in acute pancreatitis is
unknown. In this study, we tested whether increased levels of pancreatic secretory trypsin
inhibitor-I (PSTI-I) in mice could prevent secretagogue-induced pancreatitis. Methods Rat
PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice by creating a …
Background & aims Endogenous trypsin inhibitors are believed to inhibit protease activity if trypsin becomes inadvertently activated within the acinar cell. However, this action remains unproven, and the role of endogenous pancreatic trypsin inhibitors in acute pancreatitis is unknown. In this study, we tested whether increased levels of pancreatic secretory trypsin inhibitor-I (PSTI-I) in mice could prevent secretagogue-induced pancreatitis. Methods Rat PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice by creating a minigene driven by the rat elastase I enhancer/promoter. Secretagogue-induced pancreatitis was achieved by 12 hourly intraperitoneal injections of caerulein. The severity of pancreatitis was assessed by measurements of serum amylase, histologic grading, and pancreas wet weight-to-body weight ratio. Trypsinogen activation and trypsin activity were measured in pancreatic extracts. Results Targeted expression of PSTI-I to the pancreas increased endogenous trypsin inhibitor capacity by 190% (P < .01) in transgenic vs. nontransgenic mice. Caerulein administration to nontransgenic mice produced histologic evidence of acute pancreatitis, and significantly elevated serum amylase and pancreas weight ratio. In caerulein-treated transgenic mice, the histologic severity of pancreatitis was significantly reduced. There was no difference in trypsinogen activation peptide levels between caerulein-treated transgenic and nontransgenic mice. However, trypsin activity was significantly lower in transgenic mice receiving caerulein compared with nontransgenic mice. Conclusions These data demonstrate that the severity of secretagogue-induced pancreatitis is significantly ameliorated in mice with higher pancreatic levels of trypsin inhibitor. We propose that PSTI-I prevents pancreatitis by inhibiting the activity of trypsin, rather than by reducing trypsinogen activation.
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