Faculty Collaboration Database

Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med 2007 Oct 01;204(10):2439-48

Date

09/26/2007

Pubmed ID

17893198

Pubmed Central ID

PMC2118455

DOI

10.1084/jem.20070404

Scopus ID

2-s2.0-34948866150 (requires institutional sign-in at Scopus site)   263 Citations

Abstract

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.

Author List

Kerschen EJ, Fernandez JA, Cooley BC, Yang XV, Sood R, Mosnier LO, Castellino FJ, Mackman N, Griffin JH, Weiler H

Authors

Rashmi Sood PhD Associate Professor in the Pathology department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Cell Membrane Permeability
Endothelial Cells
Endotoxemia
Enzyme Activation
Lipopolysaccharides
Lymphocytes
Male
Mice
Mice, Inbred C57BL
Protein C
Protein Engineering
Sepsis
Signal Transduction
Survival Rate