Alexandra Demcsak, MD, PhD and Miklos Sahin-Toth, MD, PhD
Department of Surgery, University of California Los Angeles, Los Angeles, California
Background: Premature activation of trypsin in the pancreas is an early event in the development and progression of pancreatitis. Based on previous findings, this central step could be a potential pharmacological target to prevent the disease pathogenesis. Human cationic trypsinogen (PRSS1) mutations accelerate trypsinogen autoactivation and cause hereditary chronic pancreatitis, a devastating disease with several complications. Therapeutic drug testing requires appropriate preclinical models, which recapitulate the trypsin-dependent human disease. Available mouse models of pancreatitis in the mouse cationic trypsinogen do not adequately model the human situation. Our aim was to generate an improved preclinical mouse model, which develops trypsin-dependent spontaneous pancreatitis on a time scale that is more amenable for drug testing and detailed outcome analysis. Conclusions: 1. The increased trypsinogen autoactivation can cause various manifestations of pancreatitis, and the rate of autoactivation is the key determinant when and how pathology develops. 2. Both spontaneous and experimentally induced pancreatitis can be studied in the same mouse model (T7D22N,K24R), which makes it convenient and cost-effective; it should facilitate preclinical studies for the development of trypsin-specific therapeutic and preventive approaches against human pancreatitis.