Regulation of inflammatory responses by activated protein C: the molecular mechanism(s) and therapeutic implications

Activated protein C (APC), a natural anticoagulant, is formed from protein C by the action of the thrombinthrombomodulin (TM) complex on the endothelial cell surface. Endothelial protein C receptor augments the activation of protein C by the thrombin/TM system. APC inactivates the activated form of coagulation factors V and VIII in the presence of protein S. Administration of APC reduced the pulmonary vascular injury and hypotension as well as the coagulation abnormalities by inhibiting production of the tumor necrosis factor-alpha (TNF-alpha) in rats given endotoxin (ET). These therapeutic effects of APC could not be attributed to its anticoagulant effects. APC inhibited ET induced TNF-alpha production in human monocytes by inhibiting activation of nuclear factor k-B and activator protein-1 in vitro. Administration of the human plasmaderived APC ameliorated coagulation abnormalities without any adverse effects in patients with disseminated intravascular coagulation (DIC). Recombinant APC was reported to reduce the mortality of patients with severe sepsis, and the therapeutic effect was more marked in such patients with overt DIC than those without it. These observations strongly suggest that APC plays important roles in the regulation of inflammation as well as coagulation. Both antiinflammatory and anticoagulant properties of APC might contribute to the therapeutic usefulness in patients with severe sepsis.