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


CONCLUSIONS
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.
Busso
Nathalie
N
Laboratoire de Rhumatologie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. Nathalie.Busso@chuv.ch
Chobaz-Péclat
Veronique
V
Hamilton
Justin
J
Spee
Pieter
P
Wagtmann
Nicolai
N
So
Alexander
A
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D015153:Blotting, Western; D015942:Factor VIIa / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000502:physiology*; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D013925:Thromboplastin / Q000633:toxicity*
D044462:Receptors, Proteinase-Activated; D005337:Fibrin; D013925:Thromboplastin; D015942:Factor VIIa