Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis

Gastroenterology. 2011 Dec;141(6):2210-2217.e2. doi: 10.1053/j.gastro.2011.08.033. Epub 2011 Aug 27.


Background & aims: The role of trypsinogen activation in the pathogenesis of acute pancreatitis (AP) has not been clearly established.

Methods: We generated and characterized mice lacking trypsinogen isoform 7 (T7) gene (T(-/-)). The effects of pathologic activation of trypsinogen were studied in these mice during induction of AP with cerulein. Acinar cell death, tissue damage, early intra-acinar activation of the transcription factor nuclear factor κB (NF-κB), and local and systemic inflammation were compared between T(-/-) and wild-type mice with AP.

Results: Deletion of T7 reduced the total trypsinogen content by 60% but did not affect physiologic function. T(-/-) mice lacked pathologic activation of trypsinogen, which occurs within acinar cells during early stages of AP progression. Absence of trypsinogen activation in T(-/-) mice led to near complete inhibition of acinar cell death in vitro and a 50% reduction in acinar necrosis during AP progression. However, T(-/-) mice had similar degrees of local and systemic inflammation during AP progression and comparable levels of intra-acinar NF-κB activation, which was previously shown to occur concurrently with trypsinogen activation during early stages of pancreatitis.

Conclusions: T7 is activated during pathogenesis of AP in mice. Intra-acinar trypsinogen activation leads to acinar death during early stages of pancreatitis, which accounts for 50% of the pancreatic damage in AP. However, progression of local and systemic inflammation in AP does not require trypsinogen activation. NF-κB is activated early in acinar cells, independently of trypsinogen activation, and might be responsible for progression of AP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acinar Cells / enzymology*
  • Acinar Cells / pathology
  • Animals
  • Cell Death
  • Enzyme Activation
  • Inflammation / metabolism
  • Isoenzymes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Pancreatitis / enzymology*
  • Pancreatitis / pathology
  • Trypsinogen / metabolism*


  • Isoenzymes
  • NF-kappa B
  • Trypsinogen