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Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation.doc

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Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation

Available online /content/10/2/R42 Research article Open Access Vol 10 No 2 Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation Nathalie Busso1, Veronique Chobaz-Péclat1, Justin Hamilton2,3, Pieter Spee4, Nicolai Wagtmann4 and Alexander So1 1Laboratoire de Rhumatologie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland 2Cardiovascular Research Institute, University of California at San Francisco, Parnassus Avenue, 94143, San Francisco, California, USA 3Monash University, Australian Centre for Blood Diseases, 89 Commercial Rd, Melbourne, Victoria 3004. Australia 4Biopharmaceuticals Biology, Novo Nordisk RD, 2760 Bagsvaerd, Denmark Corresponding author: Alexander So, alexanderkai-lik.so@chuv.ch Received: 19 Dec 2007 Revisions requested: 7 Feb 2008 Revisions received: 26 Feb 2008 Accepted: 15 Apr 2008 Published: 15 Apr 2008 Arthritis Research Therapy 2008, 10:R42 (doi:10.1186/ar2400) This article is online at: /content/10/2/R42 ? 2008 Busso et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Introduction Tissue factor (TF) activation of the coagulation proteases enhances inflammation in animal models of arthritis and endotoxemia, but the mechanism of this effect is not yet fully understood – in particular, whether this is primarily due to fibrin formation or through activation of protease activated receptors (PARs). increased serum IL-6 levels. Inflammation was significantly reduced by depletion of fibrinogen (P 0.05) or platelets (P = 0.015), and by treatment with hirudin (P = 0.04) or an inhibitor of activated factor VII (P 0.001) compared with controls. PAR- 4-deficient mice exhibited significantly reduced paw swelling