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dc.contributor.authorMuley, Milind
dc.date.accessioned2018-09-28T14:00:36Z
dc.date.available2018-09-28T14:00:36Z
dc.identifier.urihttp://hdl.handle.net/10222/74263
dc.description.abstractArthritis affects many people around the world; it is a leading cause of chronic joint pain, and physical disability. Currently available drug treatments are inadequate and associated with side-effects, so there is a need for new treatments with better efficacy and safety profiles. It has been suggested that synovial inflammation plays an important role in the development of arthritic symptoms. The focus of this thesis was to assess the contribution of neutrophil elastase and proteinase-activated receptor-2 (PAR2) to the development of experimental knee joint arthritis. To this end, we evaluated the effect of local administration of neutrophil elastase on joint inflammation and pain. The role of PAR2 in mediating neutrophil elastase-induced joint inflammation and pain was assessed. Additionally, the effect of endogenous neutrophil elastase inhibition or PAR2 blockade was investigated using preclinical models of knee arthritis. Local administration of neutrophil elastase caused pro-inflammatory (an increase in leukocyte-endothelial interactions and synovial blood flow) and pro-nociceptive (a decrease in the hindpaw withdrawal threshold) effects. These effects could be blocked by the neutrophil elastase inhibitors (sivelestat or serpinA1). Neutrophil elastase-induced joint inflammation and pain can be blocked by PAR2 antagonist and do not develop in PAR2 knockout mice. Inhibition of endogenous neutrophil elastase produced anti-inflammatory effect in the kaolin/carrageenan model of acute synovitis; however, the pain response was not improved. PAR2 knockouts prevented both joint inflammation and pain in the kaolin/carrageenan model. Prophylactic inhibition of endogenous neutrophil elastase reduced Freund’s complete adjuvant (FCA)-induced chronic joint inflammation at the end of the study. FCA-induced weight-bearing deficits and withdrawal threshold were ameliorated in the acute phase of the model. In monoiodoacetate (MIA)-induced experimental osteoarthritis, we observed increased proteolytic activity of neutrophil elastase during the acute inflammatory phase of the model. Inhibition of neutrophil elastase during this inflammatory phase prevented the development of joint inflammation, pain and late-stage neuropathy in the MIA model. Modulation of PAR2 prevented MIA-induced joint inflammation, pain and neuropathy. Collectively, our findings highlight the potential of neutrophil elastase and/or PAR2 as a therapeutic target for the treatment of joint inflammation and pain associated with arthritis.en_US
dc.language.isoenen_US
dc.subjectNeutrophil elastaseen_US
dc.subjectProteinase-activated receptor-2en_US
dc.subjectJoint inflammationen_US
dc.subjectJoint painen_US
dc.subjectArthritisen_US
dc.titleROLE OF NEUTROPHIL ELASTASE AND PROTEINASE-ACTIVATED RECEPTOR-2 IN THE JOINT INFLAMMATION AND PAIN ASSOCIATED WITH EXPERIMENTAL ARTHRITISen_US
dc.date.defence2017-08-02
dc.contributor.departmentDepartment of Pharmacologyen_US
dc.contributor.degreeDoctor of Philosophyen_US
dc.contributor.external-examinerDr. Nathalie Vergnolleen_US
dc.contributor.graduate-coordinatorDr. Kishore Pasumarthien_US
dc.contributor.thesis-readerDr. Patrice Cȏtéen_US
dc.contributor.thesis-readerDr. James Fawcetten_US
dc.contributor.thesis-supervisorDr. Jason McDougallen_US
dc.contributor.ethics-approvalReceiveden_US
dc.contributor.manuscriptsNot Applicableen_US
dc.contributor.copyright-releaseYesen_US
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