title: Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways.
abstract: Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes. In each volunteer, the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase, and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases, whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation, as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes, was noted after 120 minutes, in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes, respectively. The release of t-PA coincided with activation of the fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor, observed 150 minutes after the endotoxin injection, and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early, rapidly counteracted fibrinolytic response, and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition, our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.
authors: Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands.
authors: S J
authors: SJ
authors: van Deventer
authors: H R
authors: HR
authors: Büller
authors: J W
authors: JW
authors: ten Cate
authors: L A
authors: LA
authors: Aarden
authors: C E
authors: CE
authors: Hack
authors: A
authors: A
authors: Sturk
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D003171:Complement Pathway, Classical / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004731:Endotoxins / Q000097:blood*; D004926:Escherichia coli; D006801:Humans; D007375:Interleukin-1 / Q000097:blood / Q000502:physiology; D015850:Interleukin-6 / Q000097:blood / Q000502:physiology; D007970:Leukopenia / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D010959:Tissue Plasminogen Activator