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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3176-3182.
Prepublished online as a Blood First Edition Paper on July 19, 2007; DOI 10.1182/blood-2007-02-075440.
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Submitted February 22, 2007
Accepted July 17, 2007
Protease-activated receptor-4 inhibition protects from multi-organ failure in a murine model of systemic inflammation
Sjoukje H Slofstra, Maarten F Bijlsma, Angelique P Groot, Pieter H. Reitsma, Theo Lindhout, Hugo ten Cate, and C. Arnold Spek*
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Department of Biochemistry, University of Maastricht, Maastricht, Netherlands
Department of Internal Medicine, Academic Hospital and Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, Netherlands
* Corresponding author; email: c.a.spek{at}amc.uva.nl.
Coagulation proteases may act as cell signaling molecules via protease-activated receptor (PAR) cleavage, subsequently affecting cellular and inflammatory responses. Activation of PARs in the setting of systemic inflammation and disseminated intravascular coagulation (DIC) might thus exacerbate the inflammatory response contributing to tissue and organ damage. In order to investigate the role of PAR-4 in these processes, we subjected mice to a model of systemic inflammation and DIC (Shwartzman reaction) in the absence or presence of a cell-penetrating pepducin antagonist of PAR-4 (P4pal-10). P4pal-10 dose-dependently diminished the severity of endotoxemia and preserved liver, kidney as well as lung function. Moreover, systemic inflammation and local (neutrophilic) inflammatory responses were attenuated. In vitro migration assays and P4pal-10 treatment in neutropenic mice suggest an essential role for neutrophils in PAR-4 mediated pathology. P4pal-10 treatment of thrombocytopenic mice excluded the involvement of platelets in this phenomenon. These results uncover an important role for PAR-4 in the Shwartzman reaction and suggest that inhibition of PAR-4 signaling in neutrophils could be protective in systemic inflammation and DIC.
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