title: Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: impact of a "Top-Down" approach to intestinal fibrosis in mice.
abstract: BACKGROUND
  The natural history of Crohn's disease follows a path of progression from an inflammatory to a fibrostenosing disease, with most patients requiring surgical resection of fibrotic strictures. Potent antiinflammatory therapies reduce inflammation but do not appear to alter the natural history of intestinal fibrosis. The aim of this study was to determine the relationship between intestinal inflammation and fibrogenesis and the impact of a very early "top-down" interventional approach on fibrosis in vivo.
  
  
  METHODS
  In this study we removed the inflammatory stimulus from the Salmonella typhimurium mouse model of intestinal fibrosis by eradicating the S. typhimurium infection with levofloxacin at sequential timepoints during the infection. We evaluated the effect of this elimination of the inflammatory stimulus on the natural history of inflammation and fibrosis as determined by gross pathology, histopathology, mRNA expression, and protein expression.
  
  
  RESULTS
  Fibrogenesis is preceded by inflammation. Delayed eradication of the inflammatory stimulus by antibiotic treatment represses inflammation without preventing fibrosis. Early intervention significantly ameliorates but does not completely prevent subsequent fibrosis.
  
  
  CONCLUSIONS
  This study demonstrates that intestinal fibrosis develops despite removal of an inflammatory stimulus and elimination of inflammation. Early intervention ameliorates but does not abolish subsequent fibrosis, suggesting that fibrosis, once initiated, is self-propagating, suggesting that a very early top-down interventional approach may have the most impact on fibrostenosing disease.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Hospitals, Ann Arbor, MI 48109, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Amy
authors.initials: A
authors.lastname: Luke
authors.forename: Kay
authors.initials: K
authors.lastname: Sauder
authors.forename: David S
authors.initials: DS
authors.lastname: Moons
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
authors.forename: Peter D R
authors.initials: PD
authors.lastname: Higgins
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage; D002432:Cecum / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D064704:Levofloxacin; D051379:Mice; D008808:Mice, Inbred CBA; D015242:Ofloxacin / Q000008:administration & dosage; D012481:Salmonella Infections, Animal / Q000150:complications / Q000188:drug therapy; D012486:Salmonella typhimurium; D013997:Time Factors
chemical_list: D000199:Actins; D000890:Anti-Infective Agents; D016207:Cytokines; C544013:alpha-smooth muscle actin, mouse; D064704:Levofloxacin; D015242:Ofloxacin