Thrombin functions as an inflammatory mediator through activation of its receptor.

Abstract

SummaryA rat model of inflammation was used to investigate the biological effects of thrombin. The thrombin-specific inhibitor Hirulog TM markedly attenuated the carrageenin-induced edema of the paw of the rat. Injection of thrombin into the paw also produced edema. The effect of thrombin was due to activation of its receptor; a thrombin receptor activating peptide (TRAP) reproduced the effects of thrombin in causing edema. TRAP also increased vascular permeability as demonstrated by extravasation of Evans blue and 125I-labeled serum albumin. The release of bioactive amines played an important role in mediating the TRAP-induced edema; the serotinin/histamine antagonist cryproheptadine and the histamine H2 receptor antagonist cimetidine reduced significantly the edema caused by TRAP. Treatment of rats with the mast cell degranulator 48/80 to deplete these cells of their stores of histamine and serotonin abolished completely the ability of TRAP to produce edema. Histochemical examination confirmed that TRAP treatment led to mast cell degranulation. Thus, it has been possible to demonstrate that thrombin acts as an inflammatory mediator in vivo by activating its receptor, which in turn leads to release of vasoactive amines from mast cells.

PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation

“…7B). Incubating HSCs with 50 mol/L of PAR 1 antagonist abrogated p46 Shc and p52 Shc phosphorylation induced by thrombin and SF-NH 2 (Fig. 7B).…”

“…7C). Exposure to anti-PAR 1 abolished the Shc/Grb2 complex formation triggered by thrombin and SF-NH 2 (Fig. 7C).…”

“…9,10 This cleavage event unmasks an amino terminal sequence, which in turn serves as a tethered ligand, binding intramolecularly to the body of the receptor to trigger transmembrane signaling. 9,10 Molecular cloning has identified four PARs: PAR 1 and PAR 3 , which are both preferentially activated by thrombin 11,13 ; PAR 2 , which is selectively activated by trypsin (and tryptase) 12 ; and PAR 4 , which is activated by both thrombin and trypsin. 8,10,14 -16 PAR 3 is a PAR 4 cofactor and its activity is indistinguishable from that of PAR 4 .…”

“…1 In addition to these procoagulant effects, thrombin influences the recruitment and trafficking of inflammatory cells and is a potent mitogen for a number of cell types, including endothelial cells, fibroblasts, and smooth muscle cells. [1][2][3][4] Thrombin also promotes the production and secretion of extracellular matrix proteins and influences connective tissue remodeling in normal tissues, as well as in a number of pathologic conditions including liver fibrosis. [5][6][7] As with other serine proteases, most of the cellular effects elicited by thrombin are mediated via a family of widely expressed G-protein-coupled receptors, termed protease-activated receptors (PARs).…”

Protease-activated receptors and inflammatory hyperalgesia

“…Several studies have also shown a pro-inflammatory role for PAR 1 activation (Cirino et al 1996,Vergnolle et al 1999b, and most recently, we have demonstrated that PAR 4 agonists induced oedema and granulocyte infiltration when injected into the rat paw (Hollenberg et al 2004). …”