title: Effect of oral administration of AZD8309, a CXCR2 antagonist, on the severity of experimental pancreatitis.
abstract: BACKGROUND
  Acute pancreatitis is a common gastrointestinal disorder burdened with a high mortality. Two pathophysiological events during experimental pancreatitis are thought to determine the clinical course: premature digestive protease activation and tissue infiltration by inflammatory cells. We have investigated the effect of AZD8309, a potent and orally bioavailable antagonist of the chemokine receptor CXCR2, which has been proposed to regulate the transmigration of neutrophils.
  
  
  METHODS
  Male C57BL6 mice (25-30 g) received gavage feeding of AZD8309 (50 mg/kg/BW) or mannitol (controls) twice daily starting 3 h prior to pancreatitis induction. Mild pancreatitis was induced by i.p. caerulein administration (50 μg/kg BW), severe pancreatitis by intraductal taurocholate (2%). Pancreas, lung, and serum was harvested up to 48 h after pancreatitis induction and used for histopathology, amylase, lipase, cathepsin B, trypsin, and elastase activity measurements, myeloperoxidase (MPO) content and cytokine concentrations.
  
  
  RESULTS
  Oral administration of AZD8309 significantly reduced MPO in the pancreas and lungs (8 h & 24 h) and reduced intrapancreatic trypsin and elastase activity (8 h) in caerulein-pancreatitis. In taurocholate-pancreatitis AZD8309 reduced cathepsin B activity and MPO. Serum cytokine levels were reduced by AZD8309 as well as histopathological damage.
  
  
  CONCLUSIONS
  The CXCR2 antagonist AZD8309 reduced the transmigration of neutrophils as well as intrapancreatic protease activation in experimental pancreatitis. This effect was sufficient to reduce the overall severity of the disease. CXCR2 may therefore be a viable therapeutic target and AZD8309 a suitable agent for the treatment of acute pancreatitis.
authors.affiliation: Department of Medicine A, University Medicine, Greifswald, Germany.
authors.forename: Sudarshan R
authors.initials: SR
authors.lastname: Malla
authors.affiliation: AstraZeneca R&D Mölndal, Innovative and Global Medicines, Mölndal, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Kärrman Mårdh
authors.affiliation: Department of Medicine A, University Medicine, Greifswald, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Günther
authors.affiliation: Department of Medicine A, University Medicine, Greifswald, Germany.
authors.forename: Ujjwal M
authors.initials: UM
authors.lastname: Mahajan
authors.affiliation: Department of Medicine A, University Medicine, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: D'Haese
authors.affiliation: Department of Medicine A, University Medicine, Greifswald, Germany.
authors.forename: Frank Ulrich
authors.initials: FU
authors.lastname: Weiss
authors.affiliation: Department of Medicine A, University Medicine, Greifswald, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: AstraZeneca R&D Mölndal, Innovative and Global Medicines, Mölndal, Sweden.
authors.forename: Mark Berner
authors.initials: MB
authors.lastname: Hansen
authors.affiliation: Department of Medicine A, University Medicine, Greifswald, Germany. Electronic address: mayerle@uni-greifswald.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002108:Ceruletide; D016207:Cytokines / Q000097:blood; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013656:Taurocholic Acid
chemical_list: C573077:AZD8309; D016207:Cytokines; D011743:Pyrimidines; D023063:Receptors, Interleukin-8B; D013656:Taurocholic Acid; D002108:Ceruletide; D010447:Peptide Hydrolases
keywords: Acute pancreatitis; CXCR2; IL-8 receptor; Neutrophil transmigration; Protease activations