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Collagen degradation and neutrophilic infiltration: a vicious circle in inflammatory bowel disease
  1. Pim J Koelink1,
  2. Saskia A Overbeek1,
  3. Saskia Braber1,
  4. Mary E Morgan1,
  5. Paul A J Henricks1,
  6. Mojtaba Abdul Roda1,
  7. Hein W Verspaget2,
  8. Simone C Wolfkamp3,
  9. Anje A te Velde3,
  10. Caleb W Jones4,
  11. Patricia L Jackson5,
  12. J Edwin Blalock5,
  13. Rolf W Sparidans6,
  14. John A W Kruijtzer7,
  15. Johan Garssen1,
  16. Gert Folkerts1,
  17. Aletta D Kraneveld1
  1. 1Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
  2. 2Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
  3. 3Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  4. 4Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama, USA
  5. 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and the Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
  6. 6Division of Pharmacoepidemiology & Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
  7. 7Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
  1. Correspondence to Dr Aletta D Kraneveld, Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, Utrecht 3508 TB, The Netherlands; A.D.Kraneveld{at}uu.nl

Abstract

Objective Proline–glycine–proline (PGP) has been shown to have chemotactic effects on neutrophils via CXCR2 in several lung diseases. PGP is derived from collagen by the combined action of matrix metalloproteinase (MMP) 8 and/or MMP9 and prolyl endopeptidase (PE). We investigated the role of PGP in inflammatory bowel disease (IBD).

Design In intestinal tissue from patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis, MMP8, MMP9 and PE were evaluated by ELISA, immunoblot and immunohistochemistry. Peripheral blood polymorphonuclear cell (PMN) supernatants were also analysed accordingly and incubated with collagen to assess PGP generation ex vivo. PGP levels were measured by mass spectrometry, and PGP neutralisation was achieved with a PGP antagonist and PGP antibodies.

Results In the intestine of patients with IBD, MMP8 and MMP9 levels were elevated, while PE was expressed at similar levels to control tissue. PGP levels were increased in intestinal tissue of patients with IBD. Similar results were obtained in intestine from DSS-treated mice. PMN supernatants from patients with IBD were far more capable of generating PGP from collagen ex vivo than healthy controls. Furthermore, PGP neutralisation during DSS-induced colitis led to a significant reduction in neutrophil infiltration in the intestine.

Conclusions The proteolytic cascade that generates PGP from collagen, as well as the tripeptide itself, is present in the intestine of patients with IBD and mice with DSS-induced colitis. PGP neutralisation in DSS-treated mice showed the importance of PGP-guided neutrophilic infiltration in the intestine and indicates a vicious circle in neutrophilic inflammation in IBD.

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