Abstract | BACKGROUND & AIMS: 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.
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Authors | Rajinder Dawra, Raghuwansh P Sah, Vikas Dudeja, Loveena Rishi, Rupjoyti Talukdar, Pramod Garg, Ashok K Saluja |
Journal | Gastroenterology
(Gastroenterology)
Vol. 141
Issue 6
Pg. 2210-2217.e2
(Dec 2011)
ISSN: 1528-0012 [Electronic] United States |
PMID | 21875495
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Isoenzymes
- NF-kappa B
- Trypsinogen
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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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