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.

Keywords: PRSS1, Pancreas, Inflammatory Response, Regulation, Protease, Mouse Model

Abbreviations used in this paper: AP, acute pancreatitis, NF-κB, nuclear factor κB, T7, trypsinogen isoform 7, WT, wild-type