{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:25:26Z","timestamp":1790220326036,"version":"4.1.0"},"reference-count":66,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,7,31]],"date-time":"2015-07-31T00:00:00Z","timestamp":1438300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-62740"],"award-info":[{"award-number":["MOP-62740"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2016,2]]},"abstract":"\n Background and Purpose<\/jats:title>\n Neutrophil elastase plays a crucial role in arthritis. Here, its potential in triggering joint inflammation and pain was assessed, and whether these effects were mediated by proteinase\u2010activated receptor\u20102 (PAR2).<\/jats:p>\n <\/jats:sec>\n \n Experimental Approach<\/jats:title>\n \n Neutrophil elastase (5\u2009\u03bcg) was injected into the knee joints of mice and changes in blood perfusion, leukocyte kinetics and paw withdrawal threshold were assessed. Similar experiments were performed in animals pretreated with the neutrophil elastase inhibitor sivelestat, the\n PAR<\/jats:styled-content>\n 2 antagonist\n GB8<\/jats:styled-content>\n 3, the p44\/42\n MAPK<\/jats:styled-content>\n inhibitor\n U<\/jats:styled-content>\n 0126 and in\n PAR<\/jats:styled-content>\n 2 receptor knockout (KO) mice. Neutrophil elastase activity was also evaluated in arthritic joints by fluorescent imaging and sivelestat was assessed for anti\u2010inflammatory and analgesic properties.\n <\/jats:p>\n <\/jats:sec>\n \n Key Results<\/jats:title>\n \n Intra\u2010articular injection of neutrophil elastase caused an increase in blood perfusion, leukocyte kinetics and a decrease in paw withdrawal threshold. Sivelestat treatment suppressed this effect. The\n PAR<\/jats:styled-content>\n 2 antagonist\n GB<\/jats:styled-content>\n 83 reversed neutrophil elastase\u2010induced synovitis and pain and these responses were also attenuated in\n PAR<\/jats:styled-content>\n 2\n KO<\/jats:styled-content>\n mice. The\n MAPK<\/jats:styled-content>\n inhibitor U0126 also blocked neutrophil elastase\u2010induced inflammation and pain. Active neutrophil elastase was increased in acutely inflamed knees as shown by an activatable fluorescent probe. Sivelestat appeared to reduce neutrophil elastase activity, but had only a moderate anti\u2010inflammatory effect in this model.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Implications<\/jats:title>\n \n Neutrophil elastase induced acute inflammation and pain in knee joints of mice. These changes are\n PAR<\/jats:styled-content>\n 2\u2010dependent and appear to involve activation of a p44\/42\n MAPK<\/jats:styled-content>\n pathway. Blocking neutrophil elastase,\n PAR<\/jats:styled-content>\n 2 and p44\/42\n MAPK<\/jats:styled-content>\n activity can reduce inflammation and pain, suggesting their utility as therapeutic targets.\n <\/jats:p>\n <\/jats:sec>\n \n Linked Articles<\/jats:title>\n \n This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit\n http:\/\/dx.doi.org\/10.1111\/bph.2016.173.issue-4<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bph.13237","type":"journal-article","created":{"date-parts":[[2015,7,3]],"date-time":"2015-07-03T12:01:18Z","timestamp":1435924878000},"page":"766-777","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase\u2010activated receptor\u20102"],"prefix":"10.1111","volume":"173","author":[{"given":"Milind M","family":"Muley","sequence":"first","affiliation":[{"name":"Department of Pharmacology Dalhousie University Halifax NS Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison R","family":"Reid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Dalhousie University Halifax NS 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