A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen.
OBJECTIVE
Missense mutations in human cationic trypsinogen PRSS1 are frequently detected in patients with hereditary pancreatitis, a rare genetic disease of the pancreas characterized by autodigestive necrosis, chronic inflammation, and fibrosis. To examine the link between PRSS1 mutations and the initiation and progression of hereditary pancreatitis, we have sought to generate a transgenic mouse that carries a missense mutation in the PRSS1 that is most frequently observed in patients.


METHODS
A transgenic mouse was generated in which the expression of the mouse PRSS1 mutant R122H (R122H_mPRSS1) is targeted to pancreatic acinar cells by fusion to the elastase promoter. The expression of the mutant trypsinogen was assessed by immunohistochemical staining and real-time reverse transcription polymerase chain reaction analysis. The relationship between transgene expression and inflammation was analyzed by morphologic assessment of H&E-stained tissue sections, responsiveness to cerulein-induced pancreatitis, and immunohistochemical identification of cellular and biochemical components of the inflammatory response.


RESULTS
Pancreata from transgenic mice display early-onset acinar cell injury and inflammatory cell infiltration. With progressing age, the transgenic mice develop pancreatic fibrosis and display acinar cell dedifferentiation. Moreover, the expression of R122H_mPRSS1 transgene is associated with enhanced response to cerulein-induced pancreatitis. Finally, cell-specific activation of the inflammation-associated signaling pathways, c-jun-N-terminal kinase and extracellular signal-regulated kinase, was observed in response to expression of R122H_mPRSS1.


CONCLUSIONS
These results underscore the importance of PRSS1 mutations as pathogenic mediators of hereditary pancreatitis and indicate that persistent pancreatic injury might be causally linked to chronic pancreatitis.
Archer
Herbert
H
Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York, USA.
Jura
Natalia
N
Keller
James
J
Jacobson
Matthew
M
Bar-Sagi
Dafna
D
D000818:Animals; D002108:Ceruletide / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D014362:Trypsinogen / Q000235:genetics* / Q000378:metabolism
D002108:Ceruletide; D014362:Trypsinogen; D004247:DNA