title: Farnesyltransferase regulates neutrophil recruitment and tissue damage in acute pancreatitis.
abstract: OBJECTIVE
  The signaling mechanisms controlling organ damage in the pancreas in severe acute pancreatitis (AP) remain elusive. Herein, we examined the role of farnesyltransferase signaling in AP.
  
  
  METHODS
  Pancreatitis was provoked by the infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a farnesyltransferase inhibitor FTI-277 (25 mg/kg) before pancreatitis induction.
  
  
  RESULTS
  FTI-277 decreased the blood amylase levels, pancreatic neutrophil infiltration, hemorrhage, and edema formation in the pancreas in mice challenged with taurocholate. Farnesyltransferase inhibition reduced the myeloperoxidase levels in the pancreas and lungs in response to taurocholate infusion. However, FTI-277 had no effect on the taurocholate-provoked formation of macrophage inflammatory protein-2 in the pancreas. Interestingly, farnesyltransferase inhibition abolished the neutrophil expression of macrophage-1 antigen in mice with pancreatitis. In addition, FTI-277 decreased the taurocholate-induced activation of the rat sarcoma protein in the pancreas. An important role of farnesyltransferase was confirmed in L-arginine-induced pancreatitis.
  
  
  CONCLUSIONS
  These results demonstrate that farnesyltransferase signaling plays a significant role in AP by regulating neutrophil infiltration and tissue injury via the neutrophil expression of macrophage-1 antigen. Thus, our findings not only elucidate novel signaling mechanisms in pancreatitis but also suggest that farnesyltransferase might constitute a target in the management of severe AP.
authors.affiliation: From the Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Merza
authors.forename: Darbaz
authors.initials: D
authors.lastname: Awla
authors.forename: Rundk
authors.initials: R
authors.lastname: Hwaiz
authors.forename: Milladur
authors.initials: M
authors.lastname: Rahman
authors.forename: Stefan
authors.initials: S
authors.lastname: Appelros
authors.forename: Aree
authors.initials: A
authors.lastname: Abdulla
authors.forename: Sara
authors.initials: S
authors.lastname: Regner
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000201:enzymology; D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D001120:Arginine; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D009195:Peroxidase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013656:Taurocholic Acid; D014357:Trypsin / Q000378:metabolism; D014362:Trypsinogen / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; D004791:Enzyme Inhibitors; C096856:FTI 277; D016177:Macrophage-1 Antigen; D013656:Taurocholic Acid; D014362:Trypsinogen; D001120:Arginine; D008715:Methionine; D009195:Peroxidase; D051231:Farnesyltranstransferase; D000681:Amylases; D014357:Trypsin