The Protective Role of Protein C in Endotoxin-Induced Shock.

The serine protease, activated Protein C (aPC) plays an important role in the maintenance of vascular hemostasis. Besides its ability to regulate coagulation and fibrinolysis, aPC also possesses antiinflammatory and antiapoptotic properties. Severe depletion of plasma PC and aPC contributes to sepsis pathogenesis. Although treatment with recombinant aPC benefits a subset of patients with severe sepsis, mechanisms by which aPC improves survival in these patients remain largely unknown. Using mice genetically predisposed to a severe PC deficiency, we initiated studies to further elucidate the mechanistic relationships between very low endogenous PC levels and inflammatory disease pathogenesis. Here, we show for the first time, that novel genetic dosing of PC strongly correlates with survival outcome following endotoxin (LPS) challenge in mice. Our findings provide evidence that very low endogenous levels of PC predispose mice to early onset of disseminated intravascular coagulation, thrombocytopenia, hypotensive shock, organ damage, and reduced survival after LPS challenge. Furthermore, an excessive inflammatory response is observed in very low-PC mice, but is greatly reduced in WT cohorts. Administration of recombinant human aPC to low-PC mice significantly prevents endotoxin-induced hypotensive shock and prolongs survival. This study highlights the importance of host endogenous levels of PC in predicting survival outcome following a severe acute inflammatory challenge.