Activated protein C action in inflammation

Abstract

Summary Activated protein C (APC) is a natural anticoagulant that plays an important role in coagulation homeostasis by inactivating the procoagulation factor Va and VIIIa. In addition to its anticoagulation functions, APC also has cytoprotective effects such as anti‐inflammatory, anti‐apoptotic, and endothelial barrier protection. Recently, a recombinant form of human APC (rhAPC or drotrecogin alfa activated; known commercially as ‘Xigris’) was approved by the US Federal Drug Administration for treatment of severe sepsis associated with a high risk of mortality. Sepsis, also known as systemic inflammatory response syndrome (SIRS) resulting from infection, is a serious medical condition in critical care patients. In sepsis, hyperactive and dysregulated inflammatory responses lead to secretion of pro‐ and anti‐inflammatory cytokines, activation and migration of leucocytes, activation of coagulation, inhibition of fibrinolysis, and increased apoptosis. Although initial hypotheses focused on antithrombotic and profibrinolytic functions of APC in sepsis, other agents with more potent anticoagulation functions were not effective in treating severe sepsis. Furthermore, APC therapy is also associated with the risk of severe bleeding in treated patients. Therefore, the cytoprotective effects, rather than the anticoagulant effect of APC are postulated to be responsible for the therapeutic benefit of APC in the treatment of severe sepsis.

Cellular Mechanisms of MOF During Severe Sepsis and Septic Shock

“…These clinical finding are supported by studies in sheep, demonstrating that treatment with rhAPC in endotoxin or peritoneal-induced sepsis can reduce lung edema and injury (Waerhaug et al, 2008;Wang et al, 2007). Although APC is known for its anti-coagulative effects, these alone can not account for the improved clinical outcome in septic patients, since targeting of either activated factor X, anti-thrombin or tissue factor inhibitors has failed to produce a comparative protection (Sarangi et al, 2010). As such, APC has also been described to induce several cytoprotective effects which likely contribute to its success in the treatment of sepsis.…”

“…As such, APC has also been described to induce several cytoprotective effects which likely contribute to its success in the treatment of sepsis. These mechanisms include: 1) decreasing apoptosis (Mosnier et al, 2007), 2) the ability to bind to nuclear ribonucleoproteins, thereby facilitating the clearance of nuclear material from injured and necrotic tissue (Jean-Baptiste, 2007), 3) mediating the protection of the endothelial barrier, which prevents the destructive massive infiltration of neutrophils , 4) a number anti-inflammatory effects including the decrease of tissue factor and thrombin, which in turn can induce inflammation, and the blockade of NFκB, which subsequently decreases the direct up-regulation of cytokines (Sarangi et al, 2010). Future studies, including the current multi-centered, phase III clinical trial PROWESS SHOCK (clinicaltrials.gov NCT00604214), are likely to further investigate and clarify the various mechanisms involved in APC-induced ALI protection during sepsis.…”

Activated Protein C Attenuates Systemic Lupus Erythematosus and Lupus Nephritis in MRL-Fas(lpr) Mice

“…It acts as a natural anticoagulant by inactivating the coagulation factors Va and VIIIa (4). In addition, activated protein C has antiinflammatory effects and can support the vascular endothelial barrier (5), which, altogether, has shown to be protective in severe human sepsis (6). In fact, a recombinant form of human activated protein C (Drotrecogin alfa activated; commercially known as Xigris; Lilly Deutschland, Bad Homburg, Germany) was approved in 2001 by the U.S. Food and Drug Administration for the treatment of severe sepsis and high risk of death (7).…”

“…In fact, a recombinant form of human activated protein C (Drotrecogin alfa activated; commercially known as Xigris; Lilly Deutschland, Bad Homburg, Germany) was approved in 2001 by the U.S. Food and Drug Administration for the treatment of severe sepsis and high risk of death (7). Although the precise way of action has not yet been elucidated (5,8), the immunosuppressive and cytoprotective effects of activated protein C now emerge as a potential treatment for a number of other diseases that are associated with excessive immune responses such as acute respiratory distress syndrome, multiple sclerosis, rheumatoid arthritis, brain injury, stroke, and chronic wounds (9)(10)(11)(12). A recent study reported that activated protein C was also effective in protecting against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis, where it modulates the mitochondrial apoptosis pathway via the protease-activated receptor-1 (PAR-1) and the endothelial protein C receptor (EPCR) (13).…”

Hemostatic Soluble Plasma Proteins During Acute-Phase Response and Chronic Inflammation

“…Its anticoagulant competence enhances, due to the modulation of the thrombin activity through two mechanisms, inhibition of prothrombin converting into thrombin and promotion of thrombin inversion from a procoagulant enzyme into an anticoagulant one. Inhibition of thrombin formation can also reduce thrombin's proinflammatory activities (Sarangi et al, 2010). In a complementary mode with respect to anticoagulation, the surplus clots are dissolved by proteases of the fibrinolytic system.…”