Titre
Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Busso, N.
Auteure/Auteur
Chobaz-Péclat, V.
Auteure/Auteur
Hamilton, J.
Auteure/Auteur
Spee, P.
Auteure/Auteur
Wagtmann, N.
Auteure/Auteur
So, A.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1478-6362[electronic]
Statut éditorial
Publié
Date de publication
2008
Volume
10
Numéro
2
Première page
R42
Langue
anglais
Résumé
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).
METHODS: We induced extravascular inflammation by injection of recombinant soluble murine TF (sTF1-219) in the hind paw. The effects of thrombin inhibition, fibrinogen and platelet depletion were evaluated, as well as the effects of PAR deficiency using knockout mice deficient for each of the PARs.
RESULTS: Injection of soluble TF provoked a rapid onset of paw swelling. Inflammation was confirmed histologically and by 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 (P = 0.003). In contrast, a deficiency in either PAR-1, PAR-2 or PAR-3 did not affect the inflammatory response to soluble TF injection.
CONCLUSION: Our results show that soluble TF induces acute inflammation through a thrombin-dependent pathway and both fibrin deposition and platelet activation are essential steps in this process. The activation of PAR-4 on platelets is crucial and the other PARs do not play a major role in soluble TF-induced inflammation.
METHODS: We induced extravascular inflammation by injection of recombinant soluble murine TF (sTF1-219) in the hind paw. The effects of thrombin inhibition, fibrinogen and platelet depletion were evaluated, as well as the effects of PAR deficiency using knockout mice deficient for each of the PARs.
RESULTS: Injection of soluble TF provoked a rapid onset of paw swelling. Inflammation was confirmed histologically and by 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 (P = 0.003). In contrast, a deficiency in either PAR-1, PAR-2 or PAR-3 did not affect the inflammatory response to soluble TF injection.
CONCLUSION: Our results show that soluble TF induces acute inflammation through a thrombin-dependent pathway and both fibrin deposition and platelet activation are essential steps in this process. The activation of PAR-4 on platelets is crucial and the other PARs do not play a major role in soluble TF-induced inflammation.
PID Serval
serval:BIB_6BC78CC32C70
PMID
Open Access
Oui
Date de création
2009-03-03T08:50:33.142Z
Date de création dans IRIS
2025-05-20T20:54:14Z
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Nom
BIB_6BC78CC32C70.P001.pdf
Version du manuscrit
preprint
Taille
1.12 MB
Format
Adobe PDF
PID Serval
serval:BIB_6BC78CC32C70.P001
URN
urn:nbn:ch:serval-BIB_6BC78CC32C706
Somme de contrôle
(MD5):4c973b9455497c76fa51c0ff02c8c012