title: Panhematin provides a therapeutic benefit in experimental pancreatitis.
abstract: OBJECTIVE
  Acute pancreatitis (AP) can result in pancreatic necrosis and inflammation, with subsequent multi-organ failure. AP is associated with increased neutrophil recruitment and a rise in pro-inflammatory cytokines such as TNFα. Pretreatment with haemin, results in recruitment of haem-oxygenase-1 (HO-1)(+) macrophages and protects against experimental pancreatitis. It is not clear whether modulation of HO-1 after onset of disease has a protective role. In this study, we tested the utility of Panhematin, a water-soluble haemin formulation, in activating and inducing pancreatic HO-1, and as a therapeutic agent in treating mouse acute pancreatitis.
  
  
  METHODS
  We defined the distribution of radiolabelled haemin, then used in vivo HO-1-luciferase bioluminescence imaging and the CO-release assay to test Panhematin-induced upregulation of HO-1 transcription and activity, respectively. Using two well-defined AP murine models, we tested the therapeutic benefit of Panhematin, and quantified cytokine release using a luminex assay.
  
  
  RESULTS
  Intravenously administered Panhematin induces rapid recruitment of HO-1(+) cells to the pancreas within 2 h and de novo splenic HO-1 transcription by 12 h. Despite high baseline spleen HO-1 activity, the pancreas is particularly responsive to Panhematin-mediated HO-1 induction. Panhematin-treated mice, at various time points after AP induction had significant reduction in mortality, pancreatic injury, together with upregulation of HO-1 and downregulation of pro-inflammatory cytokines and CXCL1, a potent neutrophil chemoattractant.
  
  
  CONCLUSIONS
  Despite AP-associated mortality and morbidity, no effective treatment other than supportive care exists. We demonstrate that Panhematin leads to: (i) rapid induction and activation of pancreatic HO-1 with recruitment of HO-1(+) cells to the pancreas, (ii) amelioration of AP even when given late during the course of disease, and (iii) a decrease in leucocyte infiltration and pro-inflammatory cytokines including CXCL1. The utility of Panhematin at modest doses as a therapeutic in experimental pancreatitis, coupled with its current use and safety in humans, raises the potential of its applicability to human pancreatitis.
authors.affiliation: University of Michigan Medical School, Department of Molecular & Integrative Physiology, Ann Arbor, Michigan, USA. aidah@stanford.edu
authors.forename: Aida
authors.initials: A
authors.lastname: Habtezion
authors.forename: Raymond
authors.initials: R
authors.lastname: Kwan
authors.forename: Ehsaan
authors.initials: E
authors.lastname: Akhtar
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Wanaski
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Collins
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wong
authors.forename: David K
authors.initials: DK
authors.lastname: Stevenson
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Butcher
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
mesh_terms: D000208:Acute Disease; D000818:Animals; D001120:Arginine; D002248:Carbon Monoxide / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006427:Hemin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010179:Pancreas / Q000201:enzymology; D010195:Pancreatitis / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D013154:Spleen / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D006427:Hemin; D002248:Carbon Monoxide; D001120:Arginine; D051547:Heme Oxygenase-1