Leukocyte infiltration and acinar cell
necrosis are hallmarks of severe AP, but the signaling pathways regulating
inflammation and organ injury in the pancreas remain elusive. In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL/6 mice were treated with a geranylgeranyltransferase inhibitor
GGTI-2133 (20 mg/kg) prior to induction of
pancreatitis by infusion of
taurocholate into the pancreatic duct. Pretreatment with
GGTI-2133 reduced plasma
amylase levels, pancreatic neutrophil recruitment,
hemorrhage, and
edema formation in
taurocholate-evoked
pancreatitis. Moreover, administration of
GGTI-2133 decreased the
taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with
GGTI-2133 markedly reduced levels of CXCL2 in the pancreas and
IL-6 in the plasma in response to
taurocholate challenge. Notably, geranylgeranyltransferase inhibition abolished neutrophil expression of Mac-1 in mice with
pancreatitis. Finally, inhibition of geranylgeranyltransferase had no direct effect on
secretagogue-induced activation of
trypsinogen in pancreatic acinar cells in vitro. A significant role of geranylgeranyltransferase was confirmed in an alternate model of AP induced by
L-arginine challenge. Our findings show that geranylgeranyltransferase regulates neutrophil accumulation and tissue damage via expression of Mac-1 on neutrophils and CXCL2 formation in AP. Thus, these results reveal new signaling mechanisms in
pancreatitis and indicate that targeting geranylgeranyltransferase might be an effective way to ameliorate severe AP.