Transgenic Expression of PRSS1R122H Sensitizes Mice to Pancreatitis

The Complex Role of Trypsin in Pancreatitis

“…Unlike a recently reported "invented" p.D23A mutation, 30 which increases autoactivation of cationic trypsin 50-fold in T7D23A knock-in mice, in the present model autoactivation of the recombinant p.K24R enzyme increased to approximately 5-fold. As in the study of Huang et al, 25 no spontaneous pancreatitis or intrapancreatic trypsin activation developed. When challenged in the secretagogue-induced pancreatitis model, trypsin activity in the pancreas increased less than 2-fold compared with wild-type littermates, but parameters of pancreatitis such as histologic damage, serum pancreatic enzymes, and infiltration of inflammatory cells in the pancreas and lungs were all greater in the transgenic animals.…”

“…Two manuscripts in the present issue of Gastroenterology make an attempt to overcome this apparent controversy. Huang et al 25 have generated a mouse strain that, in addition to its wild-type mouse trypsinogen-7, expresses human PRSS1 in the exocrine pancreas (controlled by a full length elastase promoter), either as a wild-type variety or with a p.R122H-mutation, the first trypsin mutation discovered in man 15 and the one with the highest degree of penetrance for chronic pancreatitis. 26 The authors induced pancreatitis in these animals via supramaximal secretagogue stimulation, by injecting bacterial lipopolysaccharide, or they put them on either high-fat or alcohol-containing diets.…”

What Do We Currently Know about the Pathophysiology of Alcoholic Pancreatitis: A Brief Review

“…The PRSS1 variant probably influences vulnerability for alcoholic pancreatitis by altering the expression of the primary trypsinogen gene. A recent study has shown that expression of the mutant form of human PRSS1 (PRSS1R122H) in transgenic mice causes more severe pancreatitis after ethanol feeding compared to control or PRSS1 gene carriers [45], thus experimentally supporting the theory of interaction between genetic and environmental risk factors. Moreover, alterations in the trypsinogen-degrading enzyme chymotrypsin C were identified (variants: p. R254W and p.K247_R254del) as they are more common in patients with alcoholic chronic pancreatitis [46].…”

Pancreatic Fibroblast Heterogeneity: From Development to Cancer

“…Notably, some of these compounds (e.g., caerulein) can be administered over a short period of time to induce acute pancreatitis, allowing researchers to study tissue recovery from acute pancreatic injury. Beyond these intervention-based models, recent work has produced genetic models of chronic pancreatitis [ 88 , 89 , 90 , 91 ]. These models display progressive pancreatic disease, either as a consequence of aging, or following an initial injury, and eventually develop the fibrosis typical of chronic pancreatitis.…”

“…These models display progressive pancreatic disease, either as a consequence of aging, or following an initial injury, and eventually develop the fibrosis typical of chronic pancreatitis. Further, several of these models utilize mutations analogous to those found in hereditary pancreatitis [ 88 , 90 , 91 ]. This provides an opportunity to study inherited risk factors of chronic pancreatitis, an avenue previously not possible with intervention-based models alone.…”