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Protease-Activated Receptor-2 activation: a major role in intestinal inflammation
  1. Eric Hyun
  1. University of Calgary, Canada
    1. Patricia Andrade-Gordon
    1. Johnson & Johnson Pharmaceutical Research Institute, United States
      1. Martin Steinhoff
      1. University of Munster, Germany
        1. Nathalie Vergnolle (nvergnol{at}ucalgary.ca)
        1. University of Calgary, Canada

          Abstract

          Background & Aims: The role of PAR2 during intestinal inflammation is still unclear due to the fact that PAR2 activating peptide had both pro- and anti-inflammatory properties. The aim of this study was to investigate the effects of PAR2 deficiency (using PAR2-deficient mice: PAR2-/-) in models of colitis, in order to elucidate the role of endogenous PAR2 in the process of inflammation in the gut.

          Methods: Colonic inflammation in wildtype and PAR2-/- mice was induced by dextran sodium sulfate, trinitrobenzene sulphonic acid (a T-helper-1 predominant model) or oxazolone (a T-helper-2 predominant model). Leukocyte recruitment (assessed by intravital microscopy) and inflammatory parameters (myeloperoxydase, macro- and microscopic damage) were assessed during the development of colitis. Lastly, the protein levels of cyclooxygenases and adhesion molecules (ICAM-1, VCAM-1, Alpha-M, Alpha-4) were assessed via western blot analysis.

          Results: In all three models of colitis, MPO activity, macroscopic damage score and bowel thickness were significantly lower in PAR2-/- mice. Changes in vessel leukocyte recruitment parameters (rolling and adhesion) were also significantly reduced in PAR2-/- compared to wildtype mice after the induction of colitis. The protein expression of adhesion molecules (ICAM-1, VCAM-1 and alpha-4) was significantly attenuated, whereas the expression of COX-1 was significantly increased in PAR2-/- challenged with TNBS-induced colitis.

          Conclusions: The role of endogenous PAR2 in the gut is pro-inflammatory and independent of T-helper-1 or -2 cytokine profile. Endogenous PAR2 activation controls leukocyte recruitment in the colon and thus appears as a new potential therapeutic target for inflammatory bowel disease treatments.

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