title: Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse--a model mimicking inflammatory bowel disease.
abstract: BACKGROUND
  In inflammatory bowel disease a defective mucosal barrier, a dysregulated immune response and an excessive reactivity against the gut microbiota are assumed to cause a breakdown of the intestinal homeostasis and lead to chronic inflammation. Piroxicam treatment is a method for induction of colitis in IL-10 k.o. mice, which integrates a dysfunction of both the intestinal barrier and the immune system. However, the translational value of this model has not been thoroughly clarified.
  
  
  OBJECTIVE
  To characterise the piroxicam-accelerated colitis (PAC) IL-10 k.o. model with respect to clinical features, pathogenic mechanisms and its ability to respond to existing therapies.
  
  
  METHODS
  The PAC IL-10k.o. model was established on a C57BL/6J background and the clinical manifestations, immunological mechanisms and efficacy of ampicillin and anti-IL-12/23p40 treatment were assessed.
  
  
  RESULTS
  The PAC IL-10 k.o. mice developed weight loss and diarrhoea, and colonoscopy revealed a thickened granulomatous mucosa. Histological evaluation of ileum and colon showed Crohn's disease-like changes with pronounced hyperplasia and focal transmural inflammation. Ileitis was also observed in piroxicam treated wild type mice. The total number of neutrophils, monocytes and natural killer cells was elevated in the blood compared to IL-10 k.o. and wild type mice, indicating a role of the innate immune system in the pathogenesis. These findings were supported by analyses of the intestinal cytokine profile. Ampicillin and anti-IL-12/23p40 treatment significantly suppressed disease in the model.
  
  
  CONCLUSIONS
  The PAC IL-10 k.o. model resembles several features of Crohn's disease and could be a useful in vivo model in preclinical research.
authors.affiliation: Novo Nordisk - LIFE In Vivo Pharmacology Centre, Frederiksberg, Denmark. Electronic address: KHLG@novonordisk.com.
authors.forename: Kristine
authors.initials: K
authors.lastname: Holgersen
authors.affiliation: Department of Histology, Novo Nordisk A/S, Maaloev, Denmark. Electronic address: PHKv@novonordisk.com.
authors.forename: Peter Helding
authors.initials: PH
authors.lastname: Kvist
authors.affiliation: Pharmacology, Novo Nordisk A/S, Maaloev, Denmark. Electronic address: HMar@novonordisk.com.
authors.forename: Helle
authors.initials: H
authors.lastname: Markholst
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark. Electronic address: akh@sund.ku.dk.
authors.forename: Axel Kornerup
authors.initials: AK
authors.lastname: Hansen
authors.affiliation: Department of Immunopharmacology, Novo Nordisk A/S, Maaloev, Denmark. Electronic address: ThLH@novonordisk.com.
authors.forename: Thomas Lindebo
authors.initials: TL
authors.lastname: Holm
mesh_terms: D000667:Ampicillin / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D003106:Colon / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D003967:Diarrhea / Q000209:etiology; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D006099:Granuloma / Q000473:pathology*; D006965:Hyperplasia / Q000473:pathology; D007082:Ileum / Q000473:pathology*; D007155:Immunologic Factors / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics; D007413:Intestinal Mucosa / Q000473:pathology*; D007694:Killer Cells, Natural; D007958:Leukocyte Count; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes; D009504:Neutrophils; D010894:Piroxicam; D015431:Weight Loss
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D016207:Cytokines; D007155:Immunologic Factors; D016753:Interleukin-10; D010894:Piroxicam; D000667:Ampicillin
keywords: COX; Crohn's disease; IL-10 k.o; Inflammatory bowel disease; Interleukin-10 knock out mouse; Meics; NSAID; PAC; Piroxicam; WT; cyclooxygenase; interleukin-10 knock out; mAb; monoclonal antibody; murine endoscopic index of colitis severity; non-steroidal anti-inflammatory drug; piroxicam-accelerated colitis; wild type