Browsing by Author "Hyun, Eric"

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    The role of endogenous proteinase-activated receptor-2 (par2) during the development of intestinal inflammation
    (2009) Hyun, Eric; Vergnolle, Nathalie
    Proteinase-activated receptor-2 (P AR2) has been shown to mediate various physiological functions of the gut. However, the exact role of P AR2 in the process of intestinal inflammation is unclear. Thus, we aimed at addressing the role of P AR2 during the development of experimental colitis. We challenged P AR2-deficient (P AR2 -/-) or wildtype (WT) mice with trinitrobenzene sulphonic acid (TNBS), dextran sodium sulphate (DSS) or oxazolone to induce experimental colitis. In three different models of colitis, PAR2 _,_ mice showed a reduction in leukocyte adherence along the colonic venules, macroscopic damages, myeloperoxidase activity, and bowel thickness as compared to WT mice. In TNBS challenged colons of PAR2 -/- mice, the expression of adhesion molecules (ICAM-1, VCAM-1, and alpha-4) was reduced whereas the expression of both cyclooxygenase-1 and -2 was increased as compared to WT mice. Next, we assessed the effects of daily administration of PAR2-AP (intracolonically) or a novel PAR2 antagonist (ENMD-1005, intraperitoneally) after DSS or TNBS challenge. None of these treatments modulated the development of colitis. ENMD-1OO5 also failed to prevent PAR2-AP-induced paw edema. We next generated chimeric mice (via bone marrow transplant) using PAR2 -/­and WT mice in order to assess the role of PAR2 expressed on the bone marrow derived cells during the development of colitis. PAR2 -/- chimeric mice, irrespective of the source of injected bone marrow cells showed a reduction in inflammatory parameters after DSS or TNBS challenge. The ability of leukocyte stimuli to induce leukocyte trafficking in P AR2 mice was also assessed. Increase in leukocyte adherence induced by ischemia/reperfusion, fMLP, or TNF-a, but not PAF, was reduced in PAR2 -/- mice as compared to WT mice. No difference in the expression of TNF-a receptor-! was observed between naive PAR2 -/- and WT mice. Lastly, incubation of endothelial cells with TNF-a (as early as 1 hour) increased the trypsin-like activity in the cell supematants, suggesting TNF-a may induce the release of potential P AR2 activating proteinases. Taken together, we conclude that PAR2 plays a pro-inflammatory role in the intestine and represents a potential therapeutic target for the treatment of inflammatory bowel disease.