Stromelysin-1 and macrophage metalloelastase expression in the intestinal mucosa of Crohn's disease patients treated with infliximab

Antonio Di Sabatino, Ulpu Saarialho-Kere, Mark G. Buckley, John N. Gordon, Paolo Biancheri, Laura Rovedatti, Gino R. Corazza, Thomas T. MacDonald, Sylvia L F Pender

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND AND AIMS: The mechanism by which anti-tumor necrosis factor (TNF)-α therapy promotes rapid closure of fistulas and mucosal wound healing in Crohn's disease (CD) remains unclear. An ex-vivo model of gut T-cell mediated injury indicated that TNF-α blockade prevents tissue damage concomitant with matrix metalloproteinase (MMP) inhibition. We, therefore, hypothesized that the chimeric anti-TNF-α antibody infliximab facilitates wound healing in CD by downregulating tissue degrading MMPs. We focused on MMP-3 (stromelysin-1) and MMP-12 (macrophage metalloelastase) as these two enzymes have been linked to connective tissue destruction in CD. METHODS: Endoscopic biopsies were taken from 10 CD patients immediately before and after 10 weeks of treatment with infliximab. Before treatment, biopsies were taken from macroscopically inflamed areas, and after treatment were collected from the same locations as before treatment. The degree of mucosal damage was assessed by using a histological scoring system. MMP transcripts were detected by in-situ hybridization on paraffin sections. MMP proteins were determined by immunoblotting on mucosal homogenates. RESULTS: Six out of 10 patients had a clinical response to infliximab. MMP-3 and MMP-12 transcripts and proteins, which were highly expressed in CD inflamed mucosa, decreased after treatment in those patients who responded to infliximab. MMP-3 and MMP-12 downregulation was accompanied by a concomitant improvement of the histologic score. No change in MMP expression was found in nonresponders. CONCLUSION: The downregulation of tissue degrading MMPs in CD mucosa may explain the wound repair capacity of infliximab in healing fistulas and ulcers.

Original languageEnglish
Pages (from-to)1049-1055
Number of pages7
JournalEuropean Journal of Gastroenterology and Hepatology
Volume21
Issue number9
DOIs
Publication statusPublished - Sep 2009

Keywords

  • Extracellular matrix
  • In-situ hybridization
  • Inflammatory bowel disease
  • Matrix metalloproteinase
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

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