THROMBIN FUNCTIONS AS AN INFLAMMATORY MEDIATOR THROUGH ACTIVATION OF ITS RECEPTOR

A rat model of inflammation was used to investigate the biological eff ects of thrombin. The thrombin-specific inhibitor Hirulog(TM) markedly attenuated the carrageenin-induced edema of the paw of the rat. Injec tion of thrombin into the paw also produced edema. The effect of throm bin was due to activation of its receptor; a thrombin receptor activat ing peptide (TRAP) reproduced the effects of thrombin in causing edema . TRAP also increased vascular permeability as demonstrated by extrava sation of Evans blue and I-125-labeled serum albumin. The release of b ioactive amines played an important role in mediating the TRAP-induced edema; the serotinin/histamine antagonist cryproheptadine and the his tamine H2 receptor antagonist cimetidine reduced significantly the ede ma caused by TRAP. Treatment of rats with the mast cell degranulator 4 8/80 to deplete these cells of their stores of histamine and serotonin abolished completely the ability of TRAP to produce edema. Histochemi cal examination confirmed that TRAP treatment led to mast cell degranu lation. Thus, it has been possible to demonstrate that thrombin acts a s an inflammatory mediator in vivo by activating its receptor, which i n turn leads to release of vasoactive amines from mast cells.