title: Role of lipopolysaccharide and cecal ligation and puncture on blood coagulation and inflammation in sensitive and resistant mice models.
abstract: The hemostatic system is severely disturbed during endotoxemia, leading to a hypercoagulable state. However, it remains uncertain to what extent hypercoagulability is the critical factor in determining the clinical course rather than just the consequence of a severe systemic inflammatory response. To answer this question, we evaluated the evolution of hemostatic and inflammatory markers, as well as histological features, in mice sensitive and resistant to two models of endotoxemia: lipopolysaccharide-injection and cecal ligation puncture. Genetic (knockout mice) and pharmacological (PJ34) blockade of the nuclear enzyme PARP-1 was used to achieve resistance to the endotoxemia. In both models, endotoxemia resulted in antithrombin deficiency, decreased platelets, and fibrin deposition in organs, which were similar in all groups of mice. By contrast, proinflammatory mediators, inflammatory cell infiltration (especially that mediated by mononuclear cells), and organ degeneration were more intense in sensitive animals. Further studies supported a negative role for the triggering of the coagulation cascade in the mortality associated with the endotoxic shock. Hirudin had a minor effect on cell infiltration and organ damage, despite causing a potent inhibition of fibrin deposition. On the other hand, a sublethal dose of lipopolysaccharide yielded significant fibrin deposition but weak activation of the inflammatory response. Our results suggest that activation of coagulation by endotoxemia is severe and independent of the inflammatory response. However, such activation may act with fibrin deposition to have a minor influence on survival in sepsis.
authors.affiliation: Department of Medicine, Centro Regional de Hemodonación, Ronda de Garay S/N, Murcia 30003, Spain. javier.corral@carm.es
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: José
authors.initials: J
authors.lastname: Yélamos
authors.forename: David
authors.initials: D
authors.lastname: Hernández-Espinosa
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Monreal
authors.forename: Ruben
authors.initials: R
authors.lastname: Mota
authors.forename: Isabel
authors.initials: I
authors.lastname: Arcas
authors.forename: Antonia
authors.initials: A
authors.lastname: Miñano
authors.forename: Pascual
authors.initials: P
authors.lastname: Parrilla
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000032:analysis; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D002432:Cecum / Q000187:drug effects / Q000293:injuries / Q000473:pathology*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008026:Ligation; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D014950:Wounds, Penetrating / Q000150:complications
chemical_list: D000991:Antithrombins; D016207:Cytokines; D008070:Lipopolysaccharides; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases