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 kappa B (NF-kappa B), 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-kappa B 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-kappa B is activated early in acinar cells, independently of trypsinogen activation, and might be responsible for progression of AP.