The Journal of Experimental Medicine
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Published online September 24, 2007
doi:10.1084/jem.20070404
The Journal of Experimental Medicine, Vol. 204, No. 10, 2439-2448
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Kerschen et al.
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ARTICLE

 Endotoxemia and sepsis mortality reduction by non-anticoagulant–activated protein C

Edward J. Kerschen1, José A. Fernandez2, Brian C. Cooley4, Xia V. Yang2, Rashmi Sood1, Laurent O. Mosnier2, Francis J. Castellino5, Nigel Mackman3, John H. Griffin2, and Hartmut Weiler1

1 Blood Research Institute, Milwaukee, WI 53226
2 Molecular and Experimental Medicine Department and 3 Immunology Department, The Scripps Research Institute, La Jolla, CA 92037
4 Orthopaedic Surgery, Medical College of Wisconsin, Milwaukee, WI 53226
5 Chemistry Department, University of Notre Dame, Notre Dame, IN 56556

CORRESPONDENCE Hartmut Weiler: hartmut.weiler{at}bcw.edu

Activated protein C (APC) reduces mortality of severe sepsis patients but increases the risk of serious bleeding. APC exerts anticoagulant activity by proteolysis of factors Va/VIIIa. APC also exerts antiinflammatory and antiapoptotic effects and stabilizes endothelial barrier function by APC-initiated cell signaling that requires two receptors, endothelial cell protein C receptor (EPCR) and protease-activated receptor 1 (PAR1). The relative importance of APC's various activities for efficacy in sepsis is unknown. We used protein engineering of mouse APC and genetically altered mice to clarify mechanisms for the efficacy of APC in mouse sepsis models. Mortality reduction in LPS-induced endotoxemia required the enzymatic active site of APC, EPCR, and PAR-1, highlighting a key role for APC's cytoprotective actions. A recombinant APC variant with normal signaling but <10% anticoagulant activity (5A-APC) was as effective as wild-type APC in reducing mortality after LPS challenge, and enhanced the survival of mice subjected to peritonitis induced by gram-positive or -negative bacteria or to polymicrobial peritoneal sepsis triggered by colon ascendens stent implantation. Thus, APC's efficacy in severe sepsis is predominantly based on EPCR- and PAR1-dependent cell signaling, and APC variants with normal cell signaling but reduced anticoagulant activities retain efficacy while reducing the risk of bleeding.

Abbreviations used: 7-AAD, 7-amino-actinomycin D; APC, activated protein C; CASP, colon ascendens stent peritonitis; EPCR, endothelial cell protein C receptor; MPO, myeloperoxidase; MW, molecular weight; PAR1, protease-activated receptor 1; TAT, thrombin–antithrombin complex; TUNEL, Tdt-mediated dUTP-biotin nick-end labeling.

J.H. Griffin and H. Weiler contributed equally to this work.

N. Mackman's present address is Dept. of Medicine, University of North Carolina, Chapel Hill, NC 27599.


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