Trends in experimental research for acute pancreatitis using genetic mouse models

Abstract

Acute pancreatitis has been considered to be an auto-digestive phenomenon resulting from the inappropriate activation of digestive enzymes within the pancreas itself. However, acute pancreatitis has many clinical aspects concerning not only auto-digestion, but also a large number of sequelae including edema, coagulation and vascular complications, infiltration of immune cells, and local and systemic inflammation. Accumulating evidence using genetic mouse models (e.g. cathepsin B KO mice, conditional transgenic mice of rat trypsinogen II, and trypsinogen 7 KO mice) suggest that active trypsin is but one component of the multifaceted response of acinar cells to injury, and that multiple pathways are activated simultaneously by various etiologies that cause pancreatitis. Interferon regulatory factor 2 (IRF2) KO mice presented an early feature of acute pancreatitis. In the acinar cells of this mouse model, pancreatic regulated exocytosis was inhibited due to the alteration of SNARE proteins, resulting in the increase of autophagy and intracellular trypsinogen activation. Clarifying the molecular mechanisms by which IRF2 regulates the exocytotic machinery and the turbulence of signaling pathways in IRF2 KO acinar cells will make it possible to elucidate the molecular basis of acute pancreatitis and the initial trigger that causes premature activation of trypsinogen.