Protection against chronic pancreatitis and pancreatic fibrosis in mice overexpressing pancreatic secretory trypsin inhibitor.
OBJECTIVE
Mutations in the gene encoding for pancreatic secretory trypsin inhibitor (PSTI) can contribute to chronic pancreatitis. In the current study, we tested whether overexpression of PSTI-I in mice protects against chronic pancreatitis and pancreatic fibrosis.


METHODS
Rat PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice. Chronic pancreatitis was achieved by intraperitoneal injection of cerulein for 10 weeks. Pancreatitis severity was assessed by histological grading of inflammatory infiltrate, atrophy, and fibrosis; quantitation of myeloperoxidase (MPO) activity; quantitative morphometric analysis of collagen content; and measurements of type I collagen, fibronectin, and transforming growth factor beta mRNA expression.


RESULTS
Cerulein administration to nontransgenic mice produced histological evidence of inflammatory infiltrate, glandular atrophy, and parenchymal fibrosis and increased collagen production, MPO activity, and collagen I and fibronectin mRNA levels. In cerulein-treated PSTI transgenic mice, there were significant reductions in inflammatory infiltrate, MPO activity, fibrosis, and collagen I and fibronectin mRNA levels. Transgenic mice treated with cerulein had significantly less collagen than nontransgenic mice.


CONCLUSIONS
The severity of chronic pancreatitis and pancreatic fibrosis is significantly reduced in mice expressing rat PSTI-I. We propose that pancreatic trypsin inhibitors play a protective role in the pancreatic response to repeated injurious events.
Nathan
Jaimie D
JD
Department of Surgery, Duke University and Durham VA Medical Centers, Durham, NC, USA.
Romac
Joelle
J
Peng
Ruth Y
RY
Peyton
Michael
M
Rockey
Don C
DC
Liddle
Rodger A
RA
D000818:Animals; D002108:Ceruletide; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D005353:Fibronectins / Q000235:genetics; D005355:Fibrosis; D020869:Gene Expression Profiling; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000235:genetics; D014359:Trypsin Inhibitor, Kazal Pancreatic
D024042:Collagen Type I; D005353:Fibronectins; D036341:Intercellular Signaling Peptides and Proteins; C504705:Spink1 protein, rat; D016212:Transforming Growth Factor beta; D014359:Trypsin Inhibitor, Kazal Pancreatic; D002108:Ceruletide; D003094:Collagen; D009195:Peroxidase