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Abstract

Coagulation proteases were tested in a rat model of acute inflammation. Subplantar injection of Factor Xa (10-30 microg) produced a time- and dose-dependent edema in the rat paw, and potentiated carrageenin-induced edema. In contrast, the homologous protease Factor IXa was ineffective. This inflammatory response was recapitulated by the Factor Xa sequence L83FTRKL88(G), which mediates ligand binding to effector cell protease receptor-1 (EPR-1), while a control scrambled peptide did not induce edema in vivo. Conversely, injection of the EPR-1-derived peptide S123PGKPGNQNSKNEPP137 (corresponding to the receptor binding site for Factor Xa) inhibited carrageenin-induced rat paw edema, while the adjacent EPR-1 sequence P136PKKRERERSSHCYP150 was without effect. EPR-1-Factor Xa-induced inflammation was characterized by fast onset and prominent perivascular accumulation of activated and degranulated mast cells, was inhibited by the histamine/serotonin antagonists cyproheptadine and methysergide, but was unaffected by the thrombin-specific inhibitor, Hirulog. These findings suggest that through its interaction with EPR-1, Factor Xa may function as a mediator of acute inflammation in vivo. This pathway may amplify both coagulation and inflammatory cascades, thus contributing to the pathogenesis of tissue injury in vivo.

Authors

G Cirino, C Cicala, M Bucci, L Sorrentino, G Ambrosini, G DeDominicis, D C Altieri

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Citations to this article in year 2003 (7)

Title and authors Publication Year
Nicotinamide inhibits endotoxin-induced monocyte tissue factor expression
JS Ungerstedt, K Heimersson, T Soderstrom, M Hansson
Journal of Thrombosis and Haemostasis 2003
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KT Tan, A Makin, GY Lip
Expert Opinion on Investigational Drugs 2003
A fibrin based model for rheumatoid synovitis
O Sánchez-Pernaute, R Largo, E Calvo, MA Alvarez-Soria, J Egido, G Herrero-Beaumont
Annals of the rheumatic diseases 2003
Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects
E Jonge, PW Friederich, GP Vlasuk, WE Rote, MB Vroom, M Levi, T der Poll
Clinical and diagnostic laboratory immunology 2003
Effects of human mast cell tryptase on the kinetics of blood clotting
M Samoszuk, M Corwin, SL Hazen
Thrombosis Research 2003
Trocarin, a blood coagulation factor Xa homologue from snake venom, causes inflammation and mitogenesis
JS Joseph, S Thirumangalathu, F Tsang, FW Wong, RM Kini
Toxicon 2003
Blockade of Tissue Factor: Treatment for Organ Injury in Established Sepsis
MS Carraway, KE Welty-Wolf, DL Miller, TL Ortel, S Idell, AJ Ghio, LC Petersen, CA Piantadosi
American journal of respiratory and critical care medicine 2003

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