Abstract
Aside from their role in hemostasis, coagulant and fibrinolytic proteases are important mediators of inflammation in diseases such as asthma, atherosclerosis, rheumatoid arthritis, and cancer. The blood circulating zymogens of these proteases enter damaged tissue as a consequence of vascular leak or rupture to become activated and contribute to extravascular coagulation or fibrinolysis. The coagulants, factor Xa (FXa), factor VIIa (FVIIa), tissue factor, and thrombin, also evoke cell-mediated actions on structural cells (e.g., fibroblasts and smooth muscle cells) or inflammatory cells (e.g., macrophages) via the proteolytic activation of protease-activated receptors (PARs). Plasmin, the principle enzymatic mediator of fibrinolysis, also forms toll-like receptor-4 (TLR-4) activating fibrin degradation products (FDPs) and can release latent-matrix bound growth factors such as transforming growth factor-β (TGF-β). Furthermore, the proteases that convert plasminogen into plasmin (e.g., urokinase plasminogen activator) evoke plasmin-independent proinflammatory actions involving coreceptor activation. Selectively targeting the receptor-mediated actions of hemostatic proteases is a strategy that may be used to treat inflammatory disease without the bleeding complications of conventional anticoagulant therapies. The mechanisms by which proteases of the coagulant and fibrinolytic systems contribute to extravascular inflammation in disease will be considered in this review.
Highlights
As part of hemostasis, the coagulation and fibrinolytic pathways regulate vascular repair by forming and degrading fibrin, respectively [1]
Other extravascular actions of coagulants and fibrinolytic proteases are less direct, such as those of plasmin, which involve the formation of fibrin degradation products (FDPs) [13] or activation of matrix metalloproteinases (MMPs) and subsequent release of matrix-bound growth factors [14] (Figure 1)
proteaseactivated receptors (PARs)-1 and PAR-2 expression is increased in synovial fibroblasts, it appears PAR-2 is the primary mediator of synovial fibroblast growth, invasion, and cytokine production [69]
Summary
The coagulation and fibrinolytic pathways regulate vascular repair by forming and degrading fibrin, respectively [1]. Aside from roles in fibrin homeostasis, several of the coagulant and fibrinolytic proteases exert potent proinflammatory and proremodelling actions in disease. These actions may be independent of fibrin formation, such as the activation of protease-activated receptor-1 (PAR-1) on extravascular cells by the coagulants, thrombin [8] and FXa [9], and the fibrinolytic mediator, plasmin [10] (Figure 1). Other extravascular actions of coagulants and fibrinolytic proteases are less direct, such as those of plasmin, which involve the formation of fibrin degradation products (FDPs) [13] or activation of matrix metalloproteinases (MMPs) and subsequent release of matrix-bound growth factors (transactivation) [14] (Figure 1)
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