title: Recombinant human activated protein C (Xigris) attenuates murine cerulein-induced acute pancreatitis via regulation of nuclear factor κB and apoptotic pathways.
abstract: OBJECTIVE
  Microvascular thrombosis occurs in severe acute pancreatitis (AP). Exploiting this knowledge, we used human recombinant activated protein C (Xigris; Eli Lilly, Indianapolis, Ind) known to preserve microvascular patency, in evaluating the role of Xigris in experimental AP.
  
  
  METHODS
  In accordance with European union experimentation regulations, AP was induced by hourly injection of cerulein 50 μg/kg body weight over 6 hours. Male rats of median weight of 231 g (range, 176-312 g) were allocated at random into groups: group 1, control; group 2, vehicle; group 3, AP; group 4, cerulein + Xigris at induction of AP and killing at 24 h; and group 5, cerulein + Xigris 24 hours after induction and killing at 48 hours. In addition to enzymatic and histological markers of pancreatic injury, apoptosis, nuclear factor κB (NF-κB) p65/IκB, cytokine response, and endothelial injury were assessed. Western blot quantified by densitometry was used to assess marker of apoptosis and endothelial injury.
  
  
  RESULTS
  Cerulein injection resulted in acute necrotizing pancreatitis. Intervention with recombinant human activated protein C did not modify coagulation parameters or lead to hemorrhage but ameliorated pancreatic injury with preservation of IκB and reduction of NF-κB p65 and modulation of apoptosis.
  
  
  CONCLUSIONS
  Our study indicates that recombinant human activated protein C ameliorates experimental cerulein-induced pancreatitis through apoptotic and NF-κB pathways without causing pancreatic hemorrhage.
authors.affiliation: Academic Hepato-pancreato-biliary Surgery Unit, University of Manchester, Manchester Biomedical Research Centre, Manchester Royal Infirmary, Manchester, UK.
authors.forename: Benoy I
authors.initials: BI
authors.lastname: Babu
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Luisa
authors.initials: L
authors.lastname: Riccardi
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.forename: Maria
authors.initials: M
authors.lastname: Galuppo
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.forename: Ajith K
authors.initials: AK
authors.lastname: Siriwardena
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002108:Ceruletide / Q000008:administration & dosage; D016207:Cytokines / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy*; D009195:Peroxidase / Q000378:metabolism; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D016207:Cytokines; D005343:Fibrinolytic Agents; D016328:NF-kappa B; D011486:Protein C; D011994:Recombinant Proteins; D008315:Malondialdehyde; D002108:Ceruletide; D009195:Peroxidase; C421124:drotrecogin alfa activated