The role of endogenous proteinase-activated receptor-2 (par2) during the development of intestinal inflammation

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dc.contributor.advisorVergnolle, Nathalie
dc.contributor.authorHyun, Eric
dc.date.accessioned2017-12-18T22:32:23Z
dc.date.available2017-12-18T22:32:23Z
dc.date.issued2009
dc.descriptionBibliography: p. 206-244en
dc.descriptionSome pages are in colour.en
dc.description.abstractProteinase-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.
dc.format.extentxv, 244 leaves : ill. ; 30 cm.en
dc.identifier.citationHyun, E. (2009). The role of endogenous proteinase-activated receptor-2 (par2) during the development of intestinal inflammation (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/4809en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/4809
dc.identifier.urihttp://hdl.handle.net/1880/105810
dc.language.isoeng
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.titleThe role of endogenous proteinase-activated receptor-2 (par2) during the development of intestinal inflammation
dc.typedoctoral thesis
thesis.degree.disciplineMedical Science
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
ucalgary.thesis.accessionTheses Collection 58.002:Box 2079 627942951
ucalgary.thesis.notesUARCen
ucalgary.thesis.uarcreleaseyen
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