The Inflammatory Actions of Coagulant and Fibrinolytic Proteases in Disease

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.

Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis

“…Plasmin forms fibrin degradation products, which acting on toll-like receptor-4 (TLR-4) can release latent matrix-bound growth factors. Furthermore, proteases that convert plasminogen into plasmin, such as urokinase plasminogen activator (uPA), demonstrate the plasmin-independent pro-inflammatory action by binding to their receptors and co-receptors [5]. …”

“…Inflammation can be both a cause and a result of induction of coagulation [1,2,3,4]. Similarly, coagulation results not only in thrombosis but also in activation of inflammatory process [1,2,5]. …”

IL-13 Augments Compressive Stress–Induced Tissue Factor Expression in Human Airway Epithelial Cells

“…Coagulation activity in the airway lumen is critical for fibrin accumulation and asthma pathogenesis (42)(43)(44), and coagulant and fibrinolytic mediators can directly mediate inflammatory responses in the lung (45). Therefore, we determined the coagulation activity of CM.…”

Angry macrophages patrol for fibrin

“…P latelets are short-lived (;8-11 days), translationally competent, and capable of premature messenger RNA (pre-mRNA) splicing into mature mRNAs. 2 They do this using a process expected to generate lariats, which are formed of normally spliced out, circularized introns. Alhasan et al 1 now report that platelet mRNAs may also undergo exon back-splicing to generate circRNAs (see figure).…”