N. Vergnolle et al., Pro- and anti-inflammatory actions of thrombin: a distinct role for proteinase-activated receptor-1 (PAR(1)), BR J PHARM, 126(5), 1999, pp. 1262-1268
1 Thrombin has well characterized pro-inflammatory actions that have recent
ly been suggested to occur via activation of its receptor, proteinase-activ
ated receptor-1 (PAR(1)).
2 In the present study, we have compared the effects of thrombin to those o
f two peptides that selectively activate the PAR(1) receptor, in a rat hind
paw oedema model. We have also examined whether or not thrombin can exert a
nti-inflammatory activity in this model.
3 Both thrombin and the two PAR(1) activating peptides induced significant
oedema in the rat hindpaw following subplantar injection.
4 The oedema induced by thrombin was abolished by pre-incubation with hirud
in, and was markedly reduced in rats in which mast cells were depleted thro
ugh treatment with compound 48/80 and in rats pretreated with indomethacin.
In contrast, administration of the PAR(1) activating peptides produced an
oedema response that was not reduced by indomethacin and was only slightly
reduced in rats pretreated with compound 48/80.
5 Co-administration of thrombin together with a PAR(1) activating receptor
resulted in a significantly smaller oedema response than that seen with the
PAR(1) activating peptide alone. This anti-inflammatory effect of thrombin
was abolished by pre-incubation with hirudin.
6 These results demonstrate that the pro-inflammatory effects of thrombin o
ccur through a mast-cell dependent mechanism that is, at least in part, ind
ependent of activation of the PAR(1) receptor. Moreover, thrombin is able t
o exert anti-inflammatory effects that are also unrelated to the activation
of PAR(1).