Ablation of phosphoinositide 3-kinase-γ reduces the severity of acute pancreatitis

In pancreatic acini, the G-protein-activated phosphoinositide 3-kinase-gamma (PI3Kgamma) regulates several key pathological responses to cholecystokinin hyperstimulation in vitro. Thus, using mice lacking PI3Kgamma, we studied the function of this enzyme in vivo in two different models of acute pancreatitis. The disease was induced by supramaximal concentrations of cerulein and by feeding mice a choline-deficient/ethionine-supplemented diet. Although the secretive function of isolated pancreatic acini was identical in mutant and control samples, in both models, genetic ablation of PI3Kgamma significantly reduced die extent of acinar cell injury/necrosis. in agreement with a protective role of apoptosis in pancreatitis, PI3Kgamma-deficient pancreata showed an increased number of apoptotic acinar cells, as determined by terminal dUTP nick-end labeling and caspase-3 activity. In addition, neutrophil infiltration within the pancreatic tissue was also reduced, suggesting a dual action of PI3Kgamma, both in the triggering events within acinar cells and in the subsequent neutrophil recruitment and activation. Finally, the lethality of the choline-deficient/ethionine-supplemented diet-induced pancreatitis was significantly reduced in mice lacking PI3Kgamma. Our results thus suggest that inhibition of PI3Kgamma may be of therapeutic value in acute pancreatitis.