Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis

Abstract

A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.

Keywords: Phosphoinositide 3-kinase; Cell signaling; Inflammation; Pathogenesis; Acute pancreatitis

Core tip: Phosphoinositide 3-kinases (PI3Ks) are a family of lipid and protein kinases implicated in intracellular signal transduction and regulation of inflammation. Recent data suggest their involvement also in the pathogenesis of acute pancreatitis. PI3Ks, and in particular the PI3Kγ isoform, have a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ modulates acinar cell apoptosis, and regulates local and systemic inflammatory responses during experimental acute pancreatitis. Specific PI3K inhibitors may therefore provide new therapies to improve the clinical course of this disease.