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.
Bibliographical noteFunding Information:
Funding Supported in part by National Institutes of Health grants RO1 DK058694 , RO1 DK 092145 , and RO1 DK093047 (to A.K.S.).
- Inflammatory Response
- Mouse Model