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

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.Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved. PMID: 21875495 Funding information This work was supported by: NIDDK NIH HHS, United States Grant ID: R01 DK 092145 NIDDK NIH HHS, United States Grant ID: R01 DK093047 NIDDK NIH HHS, United States Grant ID: R01 DK092145 NIDDK NIH HHS, United States Grant ID: R01 DK058694