title: Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis.
abstract: 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.
authors.affiliation: Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Merza
authors.forename: Erik
authors.initials: E
authors.lastname: Wetterholm
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.forename: Sara
authors.initials: S
authors.lastname: Regner
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D061354:Acinar Cells / Q000201:enzymology; D000208:Acute Disease; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D054426:Chemokine CXCL2 / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000502:physiology*; D010195:Pancreatitis / Q000188:drug therapy / Q000276:immunology*; D054876:Prenylation; D014362:Trypsinogen / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C547856:GGTI-2133; D007093:Imidazoles; D016177:Macrophage-1 Antigen; D009281:Naphthalenes; D014362:Trypsinogen; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D020830:rac1 GTP-Binding Protein; D007930:Leucine
keywords: L-arginine; chemikine; extravasation; inflammation; myeloperoxidase; pancreas