Differential Effects of Anti-cytokine Treatment on Bronchoalveolar Hemostasis in Endotoxemic Chimpanzees

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Abstract
Activation and inhibition of coagulation and fibrinolysis was analyzed in bronchoalveolar lavage (BAL) fluids obtained from endotoxin-challenged chimpanzees. The mediatory role of tumor necrosis factor-alpha (TNF- α ) and interleukin-6 (IL-6) on endotoxin-induced changes in bronchoalveolar coagulation and fibrinolysis was investigated in experiments in which the infusion of endotoxin was combined with the administration of monoclonal anti–TNF- α or anti–IL-6 antibodies. Endotoxin infusion elicited a marked increase in bronchoalveolar thrombin generation as measured by levels of prothrombin activation fragment F1 + 2 and thrombin–antithrombin complexes. Markers for intrinsic pathway activation were not detectable, suggesting that the thrombin generation was mediated by the tissue factor–dependent route. Levels of antithrombin were low before the injection of endotoxin and not detectable hereafter. The administration of anti–IL-6 antibody completely abolished the endotoxin-induced activation of bronchoalveolar coagulation, whereas treatment with anti–TNF- α antibody only partly inhibited this effect. Bronchoalveolar fibrinolytic activity, due to urokinase-type plasminogen activator (u-PA), was significantly depressed after endotoxin injection, mainly due to a striking increase in plasminogen activator inhibitor-2 levels in BAL fluid. The endotoxin-induced effects on bronchoalveolar fibrinolysis could be blocked by the simultaneous administration of anti– TNF- α antibodies. We conclude that endotoxemia results in the activation of bronchoalveolar coagulation, which is apparently mediated by the tissue factor route of coagulation activation and which may be amplified by consumption of antithrombin III. Bronchoalveolar fibrinolytic activity is significantly abolished by increased levels of mainly PAI-2 after the injection of endotoxin. The endotoxin-induced effects on bronchoalveolar coagulation appears to be mediated by IL-6, whereas TNF- α seems to be the pivotal mediator of the endotoxin-induced depression of bronchoalveolar fibrinolysis.

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