title: Genetic Deletion of Tissue Inhibitor of Metalloproteinase-1/TIMP-1 Alters Inflammation and Attenuates Fibrosis in Dextran Sodium Sulphate-induced Murine Models of Colitis.
abstract: OBJECTIVE
  Increased levels of tissue inhibitor of metalloproteinase-1 [TIMP-1] have been detected in both inflammatory and fibrotic lesions in Crohn's disease. In a murine model of chronic inflammation, fibrosis was associated with an increase in TIMP-1 and inhibition of matrix metalloproteinase [MMP]-mediated degradation. We investigated the effect of TIMP-1 deficiency in acute and chronic murine models of colitis.
  
  
  METHODS
  Colitis was induced via oral administration of dextran sodium sulphate [DSS] to B6.129S4-Timp1tm1Pds/J knock-out [KO] and C57BL/6J wild-type [WT] mice. Levels of inflammation and fibrosis were assessed and gelatin zymographies and gene expression microarrays were performed.
  
  
  RESULTS
  Compared with WT mice, TIMP-1 KO mice had higher inflammatory parameters after acute DSS administration and developed less fibrosis after chronic DSS administration. MMP-2 levels were increased in WT versus TIMP-1 KO mice with acute colitis, whereas a trend for higher proMMP-9 levels was observed in WT versus TIMP-1 KO mice with chronic colitis. In control conditions, several immune-related genes [e.g Ido1, Cldn8] were differentially expressed between young TIMP-1 KO and WT mice, but to a lesser extent between older TIMP-1 KO and WT mice. In response to DSS, the gene expression pattern was significantly different between young TIMP-1 KO and WT mice, whereas it was similar in older TIMP-1 KO and WT mice.
  
  
  CONCLUSIONS
  TIMP-1 deficiency leads to differential expression of immune-related genes and to attenuated development of fibrosis. Unravelling the role of TIMP-1 in intestinal remodelling is necessary to develop more effective and more targeted therapeutic strategies for intestinal fibrosis.
authors.affiliation: Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Breynaert
authors.affiliation: Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Magali
authors.initials: M
authors.lastname: de Bruyn
authors.affiliation: Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Arijs
authors.affiliation: Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cremer
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Martens
authors.affiliation: Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Leentje
authors.initials: L
authors.lastname: Van Lommel
authors.affiliation: Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Geboes
authors.affiliation: Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.affiliation: Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.affiliation: Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrante
authors.affiliation: Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Ceuppens
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.affiliation: Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium gert.vanassche@uzleuven.be.|University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Van Assche
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D017353:Gene Deletion; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D016264:Dextran Sulfate
keywords: Colitis; DSS; fibrosis; TIMP-1; IBD