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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 2005 (3)

Title and authors Publication Year
Effects of anticoagulant treatment on intestinal ischaemia and reperfusion injury in rats
K Olanders, A Borjesson, X Zhao, R Andersson
Acta Anaesthesiologica Scandinavica 2005
Synergistic induction of tissue factor by coagulation factor Xa and TNF: evidence for involvement of negative regulatory signaling cascades
A Hezi-Yamit, PW Wong, N Bien-Ly, LG Komuves, KS Prasad, DR Phillips, U Sinha
Proceedings of the National Academy of Sciences of the United States of America 2005
The intriguing world of prothrombin activators from snake venom
RM Kini
Toxicon 2005

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