Hereditary pancreatitis (HP) is an autosomal dominant disease that displays the features of both acute and
chronic pancreatitis. Mutations in human cationic
trypsinogen (PRSS1) are associated with HP and have provided some insight into the pathogenesis of
pancreatitis, but mechanisms responsible for the initiation of
pancreatitis have not been elucidated and the role of apoptosis and
necrosis has been much debated. However, it has been generally accepted that
trypsinogen, prematurely activated within the pancreatic acinar cell, has a major role in the initiation process. Functional studies of HP have been limited by the absence of an experimental system that authentically mimics disease development. We therefore developed a novel transgenic murine model system using wild-type (WT) human PRSS1 or two HP-associated mutants (R122H and N29I) to determine whether expression of human cationic
trypsinogen in murine acinar cells promotes
pancreatitis. The rat
elastase promoter was used to target transgene expression to pancreatic acinar cells in three transgenic strains that were generated: Tg(Ela-PRSS1)NV, Tg(Ela-PRSS1*R122H)NV and Tg(Ela-PRSS1*N29I)NV. Mice were analysed histologically, immunohistochemically and biochemically. We found that transgene expression is restricted to pancreatic acinar cells and transgenic PRSS1
proteins are targeted to the pancreatic secretory pathway. Animals from all transgenic strains developed
pancreatitis characterised by acinar cell vacuolisation, inflammatory infiltrates and
fibrosis. Transgenic animals also developed more severe
pancreatitis upon treatment with low-dose
cerulein than controls, displaying significantly higher scores for oedema,
inflammation and overall histopathology. Expression of PRSS1, WT or mutant, in acinar cells increased apoptosis in pancreatic tissues and isolated acinar cells. Moreover, studies of isolated acinar cells demonstrated that transgene expression promotes apoptosis rather than
necrosis. We therefore conclude that expression of WT or mutant human PRSS1 in murine acinar cells induces apoptosis and is sufficient to promote spontaneous
pancreatitis, which is enhanced in response to cellular insult.