Title

Platelets Protect from Septic Shock by Inhibiting Macrophage-Dependent Inflammation via the Cyclooxygenase 1 Signalling Pathway

Abstract

Although it has long been known that patients with sepsis often have thrombocytopenia and that septic patients with severe thrombocytopenia have a poor prognosis and higher mortality, the role of platelets in the pathogenesis of sepsis is poorly understood. Here we report a protective role of platelets in septic shock. We show that experimental thrombocytopenia induced by intraperitoneal injection of an anti-glycoprotein Ibα monoclonal antibody increases mortality and aggravates organ failure, whereas transfusion of platelets reduces mortality in lipopolysaccharide-induced endotoxemia and a bacterial infusion mouse sepsis model. Plasma concentrations of proinflammatory cytokines TNF-α and IL-6 are elevated by thrombocytopenia and decreased by platelet transfusion in septic mice. Furthermore, we identify that platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the COX1/PGE₂/EP4-dependent pathway. Thus, these findings demonstrate a previously unappreciated role for platelets in septic shock and suggest that platelet transfusion may be effective in treating severely septic patients.

Document Type

Article

Publication Date

10-23-2013

Notes/Citation Information

Published in Nature Communications, v. 4, article 2657, p. 1-12.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1038/ncomms3657

Funding Information

This work was supported by the American Heart Association Midwest Affiliate Grant-in-Aid 0855698G (to Z.L.) and in part supported by the American Society of Hematology (ASH) bridge Grant Award and the NIH/National Center for Research Resources Centers of Biomedical Research Excellence in Obesity and Cardiovascular Disease Grant P20 RR021954. B.X. is a recipient of the American Heart Association Postdoctoral Fellowship Award. This work was support in part by resources provided by the Lexington VA Medical Center.