DIFFERENTIAL-EFFECTS OF ANTI-CYTOKINE TREATMENT ON BRONCHOALVEOLAR HEMOSTASIS IN ENDOTOXEMIC CHIMPANZEES

Activation and inhibition of coagulation and fibrinolysis was analyzed in bronchoalveolar lavage (BAL) fluids obtained from endotoxin-challe nged chimpanzees. The mediatory role of tumor necrosis factor-alpha (T NF-alpha) and interleukin-6 (IL-6) on endotoxin-induced changes in bro nchoalveolar coagulation and fibrinolysis was investigated in experime nts in which the infusion of endotoxin was combined with the administr ation of monoclonal anti-TNF-alpha or anti-IL-6 antibodies. Endotoxin infusion elicited a marked increase in bronchoalveolar thrombin genera tion as measured by levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes. Markers for intrinsic pathway activa tion 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 hereafte r. The administration of anti-IL-6 antibody completely abolished the e ndotoxin-induced activation of bronchoalveolar coagulation, whereas tr eatment with anti-TNF-alpha antibody only partly inhibited this effect . Bronchoalveolar fibrinolytic activity, due to urokinase-type plasmin ogen activator (u-PA), was significantly depressed after endotoxin inj ection, mainly due to a striking increase in plasminogen activator inh ibitor-2 levels in BAL fluid. The endotoxin-induced effects on broncho alveolar fibrinolysis could be blocked by the simultaneous administrat ion of anti-TNF-alpha 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 whi ch may be amplified by consumption of antithrombin III. Bronchoalveola r fibrinolytic activity is significantly abolished by increased levels of mainly PAI-2 after the injection of endotoxin. The endotoxin-induc ed effects on bronchoalveolar coagulation appears to be mediated by IL -6, whereas TNF-alpha seems to be the pivotal mediator of the endotoxi n-induced depression of bronchoalveolar fibrinolysis.