Endogenous protein C has a protective role during Gram-negative pneumosepsis (melioidosis)
Version of Record online: 7 FEB 2013
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 2, pages 282–292, February 2013
How to Cite
Endogenous protein C has a protective role during Gram-negative pneumosepsis (melioidosis). J Thromb Haemost 2013; 11: 282–92., , , , , , , .
- Issue online: 7 FEB 2013
- Version of Record online: 7 FEB 2013
- Accepted manuscript online: 8 DEC 2012 04:03AM EST
- Manuscript Accepted: 21 NOV 2012
- Manuscript Received: 4 JUL 2012
- ZonMW. Grant Number: 92003504
- Stichting BeGeTu
- Netherlands Organisation for Scientific Research. Grant Number: 91610008
- activated protein C;
- lung inflammation;
Activated protein C (APC) exerts anticoagulant effects via inactivation of factors Va and VIIIa and cytoprotective effects via protease activated receptor (PAR)1. Inhibition of endogenous APC in endotoxemia and sepsis results in exacerbation of coagulation and inflammation, with consequent enhanced lethality.
We here sought to dissect the distinct roles of the anticoagulant and cytoprotective functions of endogenous APC in severe Gram-negative pneumonia-derived sepsis (melioidosis).
We infected wild-type (WT) mice with Burkholderia pseudomallei, a common sepsis pathogen in southeast Asia, and treated them with antibodies inhibiting both the anticoagulant and cytoprotective functions of APC (MPC1609) or the anticoagulant functions of APC (MAPC1591) only. Additionally, we administered SEW2871 (stimulating the S1P1-pathway downstream from PAR1) to control and MPC1609-treated mice.
MPC1609, but not MAPC1591, significantly worsened survival, increased coagulation activation, facilitated bacterial growth and dissemination and enhanced the inflammatory response. The effects of MPC1609 could not be reversed by SEW2871, suggesting that S1P1 does not play a major role in this model.
These results suggest that the mere inhibition of the anticoagulant function of APC does not interfere with its protective role during Gram-negative pneumosepsis, suggesting a more prominent role for cytoprotective effects of APC .