Blood coagulation plays a key role among numerous mediating systems that are activated in inflammation. Receptors of the PAR family serve as sensors of serine proteinases of the blood clotting system in the target cells involved in inflammation. Activation of PAR-1 by thrombin and of PAR-2 by factor Xa leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade. Certain other receptors (EPR-1, thrombomodulin, etc.), which can modulate responses of the cells activated by proteinases through PAR receptors, are also involved in the association of coagulation and inflammation together with the receptors of the PAR family. The presence of PAR receptors on mast cells is responsible for their reactivity to thrombin and factor Xa and defines their contribution to the association of inflammation and blood clotting processes.

This study was aimed at investigating the effect of prolyl-glycyl-proline (PGP) tripeptide on vascular permeability in rats with an inflammation. It was found that the peptide reduces the rat paw edema induced by a subcutaneous administration of histamine to the same extent as the conventional anti-inflammatory agent diclofenac. However, an assessment of the relative expression level of the cox-2 gene at the inflammation focus using real-time PCR showed that, in contrast to diclofenac, PGP does not affect the cox-2 gene expression. This is indicative of the fact that they have different mechanisms of action. We used the model of acute peritonitis induced by an intraperitoneal injection of thioglycolate to demonstrate that the inflammatory response of an organism is accompanied by increased vascular permeability in the tissues of the stomach and small intestine. Pre-administration (30 minutes before the induction of the inflammation) of PGP prevented this increase, whereby the level of vascular permeability, exudate volume in the peritoneal cavity, and the amount of the Evans Blue dye in this exudate remained at the control level. Therefore, these results suggest that the anti-inflammatory action of PGP is based on its ability to prevent an increase in vascular permeability.

The development of acute peritonitis in rats induced by intraperitoneal injection of thioglycollate was accompanied by a decrease in contractile function of mesenteric lymphatic vessels and impaired response to norepinephrine. Administration of proline-containing peptides after induction of inflammation significantly decreased the severity of these disorders. Our results attest to the possibility of using peptides for the correction of mesenteric microcirculatory disturbances during inflammation.

In vivo experiments on the model of wound healing showed that thrombin and thrombin receptor agonist TRAP-6 stimulated heparin secretion by mast cells in rat subcutaneous fat: the saturation of mast cells with heparin decreased, while degranulation and granulolysis increased. In vitro studies showed that TRAP-6 caused a dose-dependent release of beta-hexosaminidase from peritoneal mast cells. TRAP-6 also induced heparin release from these cells and inhibition of amidase activity of thrombin. Heparin released from mast cells had low anticoagulant activity. These data suggest that activation of mast cells with thrombin is mediated by PAR-1.

One-hour immobilization stress considerably disturbed microcirculation in the mesentery: blood flow in small mesenteric vessels decreased or stopped and numerous hemorrhages appeared. Lymphatic vessels lost spontaneous activity and did not respond to norepinephrine. Administration of Semax and glyprolines 1 h before stress decreased the severity of stress-induced microcirculatory disturbances. PGP and GP were most effective in this respect.