Platelets Protect From Lipopolysaccharide-Induced Lethal Endotoxemia by Inhibiting Macrophage-Dependent Inflammation Via the Cyclooxygenase 1 (COX1) Signaling Pathway
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AbstractAbstract 93Sepsis is a tremendous burden for health-care systems. Patients with sepsis often have low platelet counts, and septic patients with severe thrombocytopenia have a poor prognosis and higher mortality. However, the role of platelets in the pathogenesis of sepsis has not been well elucidated. We investigated the role of platelets in septic shock using a mouse model of lipopolysaccharide (LPS)-induced endotoxemia. Depletion of platelets by intraperitoneal injection of a rat anti-mouse GPIb monoclonal antibody increased mortality and aggravated organ failure in endotoxemic mice as evident by increases in plasma aminotransferase (ALT), aspartate aminotransferase (AST), Lactate dehydrogenase (LDH), and Creatine kinase (CK) concentrations, while transfusion of platelets reduced mortality. Increases in mortality rate in thrombocytopenic mice by LPS challenge was not due to inflammatory hemorrhage, because there was no significantly hemorrhage observed in brains and lungs from mice pre-treated with either control IgG or the anti-GPIba antibody and blood RBC and Hb concentrations between IgG pre-treated mice and the anti-GPIba antibody pre-treated mice were similar. TNF-a, which is produced mainly by macrophages in vivo, plays critical roles in the development of disseminated intravascular coagulation, acute respiratory distress syndrome and shock in sepsis. Our data indicate that plasma concentrations of proinflammatory cytokines, TNF-a and IL-6, were markedly increased by platelet depletion and decreased by platelet transfusion in the mice challenged with LPS. Effects of platelet depletion on TNF-a production were eliminated in the mice that macrophages were pre-depleted. Furthermore, LPS- or thrombin-activated platelets or releasates from activated platelets inhibited TNF-a and IL-6 production in macrophages in vitro. Inhibition of TNF-a and IL-6 production in macrophages by activated platelets was prevented by pre-incubation of platelets with a COX1 inhibitor aspirin. Moreover, platelets from wild type mice but not COX1 deficient mice inhibited LPS-induced TNF-a and IL-6 production in macrophages. Transfusion of COX1 deficient platelets failed to protect against endotoxemia. Washed platelets from wild-type mice or platelet releasates from thrombin-activated wild-type mice inhibited LPS-induced TNF-a and IL-6 production in macrophages lacking TXA2 receptor, TP, suggesting that a metabolite other than TXA2 is responsible for platelet inhibition of macrophage function. We found that stimulation of platelets with thrombin or LPS induced PGE2 production and pre-incubation of macrophages with an antagonist of PGE2 receptor EP4 reversed platelet inhibition on TNF-a and IL-6 production in macrophages. Our results indicate that platelets protect against septic shock by inhibiting macrophage-dependent inflammatory response 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 septic patients.Disclosures:No relevant conflicts of interest to declare.
