Intra-acinar
trypsinogen activation occurs in the earliest stages of
pancreatitis and is believed to play important roles in
pancreatitis pathogenesis. However, the exact role of intra-acinar
trypsin activity in
pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar
trypsin activity on the development of
pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant
trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated
trypsin had no significant effect on triggering spontaneous
pancreatitis. Instead, several protective compensatory mechanisms, including
SPINK1 and
heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe
acute pancreatitis, compared with control mice, when challenged with
caerulein. Elevated tissue
edema, serum
amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased
trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal
atrophy and cell loss,
fibrosis, and fatty replacement. These changes were not observed in control mice treated with
caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human
chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of
trypsinogen plays an important role in the initiation and progression of both acute and
chronic pancreatitis. NEW & NOTEWORTHY
Trypsinogen is activated early in
pancreatitis. However, the roles of
trypsin in the development of
pancreatitis have not been fully addressed. Using a genetic approach, we showed
trypsin activity is critical for the severity of both acute and
chronic pancreatitis.