Factor XII plays a pathogenic role in organ failure and death in baboons challenged with Staphylococcus aureus.

Autor:	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., Regmi G; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK., Lupu C; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK., Georgescu C; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK., Simmons JH; Michale E. Keeling Center for Comparative Medicine and Research, University of Texas MD Anderson Cancer Center, Bastrop, TX., Wallisch M; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR.; Aronora, Inc, Portland, OR., Kohs TCL; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR., Shatzel JJ; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR.; Division of Hematology & Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR., Olson SR; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR.; Division of Hematology & Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR., Lorentz CU; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR.; Aronora, Inc, Portland, OR., Puy C; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR., Tucker EI; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR.; Aronora, Inc, Portland, OR., Gailani D; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN., Strickland S; Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY; and., Gruber A; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR.; Aronora, Inc, Portland, OR.; Division of Hematology & Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR., McCarty OJT; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR.; Division of Hematology & Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR., Lupu F; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.; Department of Cell Biology.; Department of Pathology, and.; Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Jul 15; Vol. 138 (2), pp. 178-189.
DOI:	10.1182/blood.2020009345
Abstrakt:	Activation of coagulation factor (F) XI promotes multiorgan failure in rodent models of sepsis and in a baboon model of lethal systemic inflammation induced by infusion of heat-inactivated Staphylococcus aureus. Here we used the anticoagulant FXII-neutralizing antibody 5C12 to verify the mechanistic role of FXII in this baboon model. Compared with untreated control animals, repeated 5C12 administration before and at 8 and 24 hours after bacterial challenge prevented the dramatic increase in circulating complexes of contact system enzymes FXIIa, FXIa, and kallikrein with antithrombin or C1 inhibitor, and prevented cleavage and consumption of high-molecular-weight kininogen. Activation of several coagulation factors and fibrinolytic enzymes was also prevented. D-dimer levels exhibited a profound increase in the untreated animals but not in the treated animals. The antibody also blocked the increase in plasma biomarkers of inflammation and cell damage, including tumor necrosis factor, interleukin (IL)-1β, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, nucleosomes, and myeloperoxidase. Based on clinical presentation and circulating biomarkers, inhibition of FXII prevented fever, terminal hypotension, respiratory distress, and multiorgan failure. All animals receiving 5C12 had milder and transient clinical symptoms and were asymptomatic at day 7, whereas untreated control animals suffered irreversible multiorgan failure and had to be euthanized within 2 days after the bacterial challenge. This study confirms and extends our previous finding that at least 2 enzymes of the contact activation complex, FXIa and FXIIa, play critical roles in the development of an acute and terminal inflammatory response in baboons challenged with heat-inactivated S aureus. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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