Pro- and anti-inflammatory actions of thrombin:: a distinct role for proteinase-activated receptor-1 (PAR1)

1 Thrombin has well characterized pro-inflammatory actions that have recently been suggested to occur via activation of its receptor, proteinase-activated receptor-1 (PAR(1)). 2 In the present study, we have compared the effects of thrombin to those of two peptides that selectively activate the PAR(1) receptor, in a rat hindpaw oedema model. We have also examined whether or not thrombin can exert anti-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 hirudin, and was markedly reduced in rats in which mast cells were depleted through 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 occur through a mast-cell dependent mechanism that is, at least in part, independent of activation of the PAR(1) receptor. Moreover, thrombin is able to exert anti-inflammatory effects that are also unrelated to the activation of PAR(1).