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.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Saha Cardiovascular Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Binggang
authors.initials: B
authors.lastname: Xiang
authors.forename: Guoying
authors.initials: G
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.forename: Xiang-An
authors.initials: XA
authors.lastname: Li
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Sidney W
authors.initials: SW
authors.lastname: Whiteheart
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology / Q000276:immunology*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000276:immunology; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology; D017713:Platelet Transfusion; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000276:immunology; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone