title: Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice.
abstract: Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Bane
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ivanov
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.|Department of Bioengineering and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Matafonov
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
authors.affiliation: Aronora, Inc., Portland, Oregon, United States of America.
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.affiliation: National Institute of Allergy and Infectious Disease, Bethesda, Maryland, United States of America.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smiley
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
authors.affiliation: Aronora, Inc., Portland, Oregon, United States of America.|Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Andras
authors.initials: A
authors.lastname: Gruber
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Gailani
mesh_terms: D000818:Animals; D060085:Coinfection / Q000201:enzymology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation; D005173:Factor XI Deficiency / Q000378:metabolism*; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism*; D018805:Sepsis / Q000201:enzymology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D010447:Peptide Hydrolases