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

AbstractBACKGROUND & 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.
AuthorsRajinder Dawra, Raghuwansh P Sah, Vikas Dudeja, Loveena Rishi, Rupjoyti Talukdar, Pramod Garg, Ashok K Saluja
JournalGastroenterology (Gastroenterology) Vol. 141 Issue 6 Pg. 2210-2217.e2 (Dec 2011) ISSN: 1528-0012 [Electronic] United States
PMID21875495 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Isoenzymes
  • NF-kappa B
  • Trypsinogen
Topics
  • Acinar Cells (enzymology, pathology)
  • Animals
  • Cell Death
  • Enzyme Activation
  • Inflammation (metabolism)
  • Isoenzymes (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B (metabolism)
  • Pancreatitis (enzymology, pathology)
  • Trypsinogen (metabolism)

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