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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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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Protease-activated receptor-4 inhibition protects from multiorgan failure in a murine model of systemic inflammation

Sjoukje H. Slofstra1, Maarten F. Bijlsma1, Angelique P. Groot1, Pieter H. Reitsma1, Theo Lindhout2, Hugo ten Cate3, and C. Arnold Spek1

1 Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; 2 Department of Biochemistry; and 3 Department of Internal Medicine, Academic Hospital and Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands

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. 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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