Abstract
Inflammatory diseases of the pancreas have no specific therapy. Discovery of the genetic basis of chronic pancreatitis identified the digestive enzyme trypsin as a therapeutic target. Preclinical testing of trypsin inhibition has been hampered by the lack of animal models. Here we report the T7D23A knock-in mouse, which carries a heterozygous p.D23A mutation in mouse cationic trypsinogen (isoform T7). This trypsinogen mutant autoactivates to trypsin 50-fold faster than wild type. T7D23A mice develop spontaneous acute pancreatitis with edema, necrosis and serum amylase elevation at an early age followed by progressive atrophic chronic pancreatitis with acinar cell loss, fibrosis, dilated ducts and adipose replacement. Markedly elevated trypsin activity is apparent at first signs of pancreatitis and persists into later stages of the disease. This remarkable model provides in vivo proof of concept that trypsinogen autoactivation can drive onset and progression of chronic pancreatitis and therapy should be directed against intra-pancreatic trypsin.
Highlights
Inflammatory diseases of the pancreas have no specific therapy
To model chronic pancreatitis associated with increased trypsinogen autoactivation in the mouse, we set out to mutate the endogenous cationic trypsinogen in a manner that increases its autoactivation
We chose to mutate this position because our previous studies on hereditary pancreatitis-associated mutations showed that the analogous mutation p.D22G strongly stimulated autoactivation of human cationic trypsinogen (PRSS1) and this effect was independent of CTRC4
Summary
Inflammatory diseases of the pancreas have no specific therapy. Discovery of the genetic basis of chronic pancreatitis identified the digestive enzyme trypsin as a therapeutic target. Transgenic mice carrying p.R122H-mutated mouse T8 trypsinogen were described to exhibit features of acute and chronic pancreatitis, this promising strain was eventually lost to time[7]. Increased trypsinogen autoactivation in these mice gives rise to spontaneous pancreatic pathology that recapitulates key phenotypic features of human acute and chronic pancreatitis.
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