title: Heme oxygenase 1-generated carbon monoxide and biliverdin attenuate the course of experimental necrotizing pancreatitis.
abstract: OBJECTIVE
  The cytoprotective enzyme heme oxygenase 1 (HO-1) is highly up-regulated in acute pancreatitis (AP). In this study, we tested its metabolites as potential therapeutic agents for AP in rats.
  
  
  METHODS
  Acute necrotizing pancreatitis was induced by retrograde intraductal injection of sodium taurocholate in rats. Biliverdin hydrochloride (BV HCl) (50 μmol/kg subcutaneously), the carbon monoxide, donor methylene chloride (MC) (500 mg/kg orally), or iron-chelating desferrioxamine (DFO) (125 mg/kg subcutaneously) were administered in a therapeutic manner starting with the first dose 4 hours after taurocholate injection to mimic the effects of HO-1 metabolites.
  
  
  RESULTS
  Administration of BV HCl, MC, or DFO showed significant reduction of inflammatory activity in comparison to controls leading to lower myeloperoxidase activity in the pancreas, less edema, lower ascites volumes, and preservation of tissue integrity (P < 0.05). Administration of either BV HCl or MC markedly increased 5-day survival rate (70% and 75% vs 40%; P < 0.05), whereas DFO had no significant effect on survival (60%). When given in therapeutic manner, all 3 substances led to diminished nuclear factor κB activity in the pancreas (P < 0.05).
  
  
  CONCLUSIONS
  Therapeutic use of BV HCl and MC led to marked reduction of mortality in experimental pancreatitis. Thus, HO-1 metabolites may present a novel therapeutic approach in AP treatment.
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Nuhn
authors.forename: Tomas
authors.initials: T
authors.lastname: Mitkus
authors.forename: Güralp O
authors.initials: GO
authors.lastname: Ceyhan
authors.forename: Beat M
authors.initials: BM
authors.lastname: Künzli
authors.forename: Frank
authors.initials: F
authors.lastname: Bergmann
authors.forename: Lars
authors.initials: L
authors.lastname: Fischer
authors.forename: Nathalia
authors.initials: N
authors.lastname: Giese
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Pascal O
authors.initials: PO
authors.lastname: Berberat
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001201:Ascites / Q000201:enzymology / Q000517:prevention & control; D001664:Biliverdine / Q000008:administration & dosage / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004487:Edema / Q000201:enzymology / Q000517:prevention & control; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007279:Injections, Subcutaneous; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D008752:Methylene Chloride / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D007502:Iron Chelating Agents; D016328:NF-kappa B; D008752:Methylene Chloride; D013656:Taurocholic Acid; D002248:Carbon Monoxide; D009195:Peroxidase; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D003676:Deferoxamine; D001664:Biliverdine