Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways.

Autor:	Popescu NI; Department of Arthritis and Clinical Immunology and., Silasi R; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK., Keshari RS; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK., Girton A; Department of Arthritis and Clinical Immunology and.; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK., Burgett T; Department of Arthritis and Clinical Immunology and., Zeerleder SS; Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.; Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands., Gailani D; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN; and., Gruber A; Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR., Lupu F; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK., Coggeshall KM; Department of Arthritis and Clinical Immunology and.; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2018 Aug 23; Vol. 132 (8), pp. 849-860. Date of Electronic Publication: 2018 Jun 19.
DOI:	10.1182/blood-2017-10-813618
Abstrakt:	Anthrax infections exhibit progressive coagulopathies that may contribute to the sepsis pathophysiology observed in fulminant disease. The hemostatic imbalance is recapitulated in primate models of late-stage disease but is uncommon in toxemic models, suggesting contribution of other bacterial pathogen-associated molecular patterns (PAMPs). Peptidoglycan (PGN) is a bacterial PAMP that engages cellular components at the cross talk between innate immunity and hemostasis. We hypothesized that PGN is critical for anthrax-induced coagulopathies and investigated the activation of blood coagulation in response to a sterile PGN infusion in primates. The PGN challenge, like the vegetative bacteria, induced a sepsis-like pathophysiology characterized by systemic inflammation, disseminated intravascular coagulation (DIC), organ dysfunction, and impaired survival. Importantly, the hemostatic impairment occurred early and in parallel with the inflammatory response, suggesting direct engagement of coagulation pathways. PGN infusion in baboons promoted early activation of contact factors evidenced by elevated protease-serpin complexes. Despite binding to contact factors, PGN did not directly activate either factor XII (FXII) or prekallikrein. PGN supported contact coagulation by enhancing enzymatic function of active FXII (FXIIa) and depressing its inhibition by antithrombin. In parallel, PGN induced de novo monocyte tissue factor expression in vitro and in vivo, promoting extrinsic clotting reactions at later stages. Activation of platelets further amplified the procoagulant state during PGN challenge, leading to DIC and subsequent ischemic damage of peripheral tissues. These data indicate that PGN may be a major cause for the pathophysiologic progression of Bacillus anthracis sepsis and is the primary PAMP behind the pathogen-induced coagulopathy in late-stage anthrax. (© 2018 by The American Society of Hematology.)
Databáze:	MEDLINE
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