title: Protective roles for fibrin, tissue factor, plasminogen activator inhibitor-1, and thrombin activatable fibrinolysis inhibitor, but not factor XI, during defense against the gram-negative bacterium Yersinia enterocolitica.
abstract: Septic infections dysregulate hemostatic pathways, prompting coagulopathy. Nevertheless, anticoagulant therapies typically fail to protect humans from septic pathology. The data reported in this work may help to explain this discrepancy by demonstrating critical protective roles for coagulation leading to fibrin deposition during host defense against the Gram-negative bacterium Yersinia enterocolitica. After i.p. inoculation with Y. enterocolitica, fibrinogen-deficient mice display impaired cytokine and chemokine production in the peritoneal cavity and suppressed neutrophil recruitment. Moreover, both gene-targeted fibrinogen-deficient mice and wild-type mice treated with the anticoagulant coumadin display increased hepatic bacterial burden and mortality following either i.p. or i.v. inoculation with Y. enterocolitica. Mice with low tissue factor activity succumb to yersiniosis with a phenotype similar to fibrin(ogen)-deficient mice, whereas factor XI-deficient mice show wild-type levels of resistance. Mice deficient in plasminogen activator inhibitor-1 or thrombin-activatable fibrinolysis inhibitor display modest phenotypes, but mice deficient in both plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor succumb to yersiniosis with a phenotype resembling fibrin(ogen)-deficient mice. These findings demonstrate critical protective roles for the tissue factor-dependent extrinsic coagulation pathway during host defense against bacteria and caution that therapeutics targeting major thrombin-generating or antifibrinolytic pathways may disrupt fibrin-mediated host defense during Gram-negative sepsis.
authors: Trudeau Institute, Saranac Lake, NY 12983, USA.
authors: Deyan
authors: D
authors: Luo
authors: Frank M
authors: FM
authors: Szaba
authors: Lawrence W
authors: LW
authors: Kummer
authors: Edward F
authors: EF
authors: Plow
authors: Nigel
authors: N
authors: Mackman
authors: David
authors: D
authors: Gailani
authors: Stephen T
authors: ST
authors: Smiley
mesh_terms: D000818:Animals; D025901:Carboxypeptidase B2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005172:Factor XI; D005337:Fibrin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000628:therapy; D058258:Serpin E2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015009:Yersinia Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D015008:Yersinia enterocolitica / Q000276:immunology* / Q000378:metabolism
chemical_list: D058258:Serpin E2; C511869:Serpine2 protein, mouse; D005337:Fibrin; D005172:Factor XI; D013925:Thromboplastin; D025901:Carboxypeptidase B2