Ablation of phosphoinositide 3-kinase-gamma reduces the severity of acute pancreatitis.
In pancreatic acini, the G-protein-activated phosphoinositide 3-kinase-gamma (PI3K gamma) regulates several key pathological responses to cholecystokinin hyperstimulation in vitro. Thus, using mice lacking PI3K gamma, 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 PI3K gamma significantly reduced the extent of acinar cell injury/necrosis. In agreement with a protective role of apoptosis in pancreatitis, PI3K gamma-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 PI3K gamma, 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 PI3K gamma. Our results thus suggest that inhibition of PI3K gamma may be of therapeutic value in acute pancreatitis.
Lupia
Enrico
E
Dipartimento di Fisiopatologia Clinica, Università di Torino, Via Genova 3, 10126 Torino, Italy. elupia@molinette.piemonte.it
Goffi
Alberto
A
De Giuli
Paolo
P
Azzolino
Ornella
O
Bosco
Ornella
O
Patrucco
Enrico
E
Vivaldo
Maria Cristina
MC
Ricca
Marco
M
Wymann
Matthias P
MP
Hirsch
Emilio
E
Montrucchio
Giuseppe
G
Emanuelli
Giorgio
G
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002108:Ceruletide / Q000633:toxicity; D002796:Choline Deficiency; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004032:Diet; D019587:Dietary Supplements; D005001:Ethionine / Q000008:administration & dosage; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D009504:Neutrophils / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015996:Survival Rate
D053148:Caspase 3; D020169:Caspases; D002108:Ceruletide; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005001:Ethionine; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C546764:Pik3cg protein, mouse; C505409:Casp3 protein, mouse