Thromb Haemost 2007; 98(05): 1118-1126
DOI: 10.1160/TH07-01-0052
Animal Models
Schattauer GmbH

Activated protein C downregulates p38 mitogen-activated protein kinase and improves clinical parameters in an in-vivo model of septic shock

Marcel F. Nold
1   Departments of Pediatrics, J.W. Goethe-University Hospital, Frankfurt
,
Claudia A. Nold-Petry
4   Pharmazentrum Frankfurt / ZAFES, J.W. Goethe-University Hospital, Frankfurt;
5   Pediatric Heart Center, J. Liebig-University Hospital, Giessen, Germany
,
Doris Fischer
1   Departments of Pediatrics, J.W. Goethe-University Hospital, Frankfurt
,
Bernd Richter
2   Pediatric Surgery, J.W. Goethe-University Hospital, Frankfurt
,
Roman Blaheta
3   Urology, J.W. Goethe-University Hospital, Frankfurt
,
Josef Pfeilschifter
4   Pharmazentrum Frankfurt / ZAFES, J.W. Goethe-University Hospital, Frankfurt;
,
Heiko Muhl
4   Pharmazentrum Frankfurt / ZAFES, J.W. Goethe-University Hospital, Frankfurt;
,
Dietmar Schranz
5   Pediatric Heart Center, J. Liebig-University Hospital, Giessen, Germany
,
Alex Veldman
5   Pediatric Heart Center, J. Liebig-University Hospital, Giessen, Germany
› Author Affiliations

Financial support: This work was supported by an unrestricted research grant to the Pediatric Heart Center, J. Liebig University, Giessen. The animals and laboratory supplies were provided by the Pharmazentrum Frankfurt. Protein C zymogen was kindly provided by Baxter, Vienna, Austria.
Further Information

Publication History

Received 24 January 2007

Accepted after resubmission 29 July 2007

Publication Date:
30 November 2017 (online)

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Summary

Despite the success of the anti-coagulant protease protein C (PC) in treating septic shock in humans, the signaling pathways used are still unclear. To explore the effects of treatment with PC zymogen and its activated form aPC in a setting of sepsis, we employed a piglet model of endotoxic shock. In the aPC group, we observed a 65%-90% reduction in plasmaTNF-alpha levels and a concomitant clinical improvement. Unexpectedly, administration of aPC also resulted in stabilization of the plasma pH above 7.2. Moreover, phosphorylated p38 mitogen-activated protein kinase (p38MAPK) was virtually absent in the livers of those piglets receiving aPC. In cultured human umbilical vein endothelial cells, we observed that nanomolar concentrations of PC and aPC inhibited the phosphorylation of p38MAPK. Furthermore, we showed that the regulation of the pro-apoptotic cell cycle regulator p53 by PC and aPC is dependent on the reduction of p38MAPK activation. The transduction of these effects involves all three receptors associated with protein C signaling, namely endothelial protein C receptor, protease-activated receptor 1, and sphingosine 1-phosphate receptor 1. Ultimately, this study elucidates novel signaling pathways regulated by protein C and emphasises the pivotal importance of its multiple modes of action beyond anticoagulation. APC’s clinical success may, in part, be due to p38MAPK inhibition.