The roles of thrombin and protease-activated receptors in inflammation

Abstract

Inflammation and coagulation constitute two host defence systems with complementary physiological roles in limiting tissue damage, restoring homeostasis and eliminating invading pathogens, functions reliant on effective regulation of both processes at a variety of levels. Dysfunctional activation or regulation of either pathway may lead to pathology and contribute to human diseases as diverse as myocardial infarction and septic shock. The serine protease thrombin, a key protein in the coagulation pathway, can activate cellular signalling directly via proteolytic cleavage of the N-terminal domain of a family of G-protein-coupled receptors, or indirectly through the generation of molecules such as activated protein C. These events transmit signals to many cell types and can elicit the production of various pro-inflammatory mediators such as cytokines, chemokines, and growth factors, thereby influencing cell activation, differentiation, survival and migration. This review discusses recent progress in understanding how thrombin and protease activated receptors (PAR) influence biological processes, highlighting the detrimental and protective cellular effects of thrombin and its signalling pathways. Liang Ma AbstractInflammation and coagulation constitute two host defence systems with complementary physiological roles in limiting tissue damage, restoring homeostasis and eliminating invading pathogens, functions reliant on effective regulation of both processes at a variety of levels. Dysfunctional activation or regulation of either pathway may lead to pathology and contribute to human diseases as diverse as myocardial infarction and septic shock.

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

“…T he protease a-thrombin plays a central role in linking blood coagulation with platelet activation and inflammation [1][2][3] . Thrombin has pleiotropic effects within the vasculature, principally through the generation of fibrin and via the stimulation of cells through cleavage of protease-activated receptors (PARs).…”

“…11), proangiogenic mediators such as transforming growth factor-b (ref. 3) and pro-adhesive molecules including intercellular adhesion molecule-1 (ICAM-1) (refs 12,13) and P-selectin 12 that act cooperatively to enhance leukocyte recruitment and inflammation 3 . However, the relative importance of these thrombin-initiated signalling events in endothelial cells, relative to the activation of platelets, in promoting efficient recruitment and trafficking of leukocytes to sites of endothelial perturbation remains poorly defined.…”

Biocompatibility and Biotolerability Assessment of Microspheres Using a Whole Blood Model

“…Thrombin converts subsequently fibrinogen to fibrin leading clot formation. The biological function of the coagulation system is to preserve blood hemostasis, but also to play a role in inflammatory events [47][48][49][50][51][52][53][54]. In addition, platelets play an important role in coagulation as well as in inflammation [55][56][57][58].…”

Inflammation and Acute Phase Proteins in Haemostasis

“…Many in vitro observations point to a role of coagulation proteases in upregulating the expression of proinflammatory mediators [10]. The most important mechanism by which coagulation proteases influence inflammation is by binding to protease activated receptors (PARs), of which four types (PAR 1 to 4) have been identified, all belonging to the family of transmembrane domain, G-protein-coupled receptors [11]. Tissue factor is also a potential mediator of intracellular signaling of established inflammatory pathways, functioning as an intermediate for factor VIIa-induced activation of mitogen-activated protein kinases and calcium signalling [12].…”