Endotoxic shock is associated with a coagulopathy, organ failure, and death. Tissue factor (TF) expression by monocytes exposed to bacterial endotoxin (lipopolysaccharide [LPS]) may mediate the coagulopathy and contribute to the high mortality of this disease. We examined the role of the LPS-binding protein (LBP)/CD14 receptor pathway in the LPS induction of TF expression in human monocytic THP-1 cells and peripheral blood monocytes. In THP-1 cells, the threshold concentration of LPS required to induce TF activity in serum-free medium was reduced 20-fold by purified LBP, which also enhanced TF mRNA synthesis. Similarly, monocytes cultured in the presence of serum were induced to S eptic shock syndrome, mediated by bacterial endotoxin (lipopolysaccharide [LPS]), is often associated with the development of coagulation disorders including microvascular thrombosis and disseminated intravascular coagulation.12 The pathophysiology of septic coagulopathy is intimately linked to the expression of the cellular procoagulant tissue factor (TF). In animal models, disseminated intravascular coagulation is induced by administration of either LPS or TF and is prevented by anti-TF antibodies.3 ' 4 Moreover, inhibition of TF activity in a baboon model of lethal septic shock using a monoclonal antibody attenuates the coagulopathy and protects against lethality, indicating that TF is a mediator of fatal bacteremic shock.
5Monocytes are the only circulating cell type that can be induced to express TF. 6 These cells may therefore represent the primary source of TF within the vasculature of patients with sepsis.2 In patients with meningococcal infection increased monocyte TF expression directly correlates with mortality.7 Experimental studies with leopine, 8 murine, 9 and porcine 10 models of septic shock indicate that monocytes from septic groups consistently express higher levels of TF activity than monocytes from control groups. Moreover, monocytes from rabbits pretreated with endotoxin are thrombogenic and produce pulmonary emboli and death when infused intravenously into untreated rabbits.
11TF expression is induced on the surface of human peripheral blood monocytes by exposure to LPS in
Exposure of rabbit peritoneal exudate macrophages (PEM) or whole blood to picomolar concentrations ofLPS induces adaptation or hyporesponsiveness to LPS. Because of the importance of plasma LPS-binding protein (LBP) and the macrophage cell membrane protein CD14 in recognition of LPS, we examined the effect of LBP on LPS-induced adaptation in PEM. PEM exposed to LPS in the presence of LBP for 8 h were markedly less responsive to subsequent stimulation by LPS than monocytes/macrophages (M+) adapted in the absence of LBP. LPS-induced expression of TNF was sharply reduced in LBP-LPS-adapted PEM, but in contrast these cells remained fully responsive to Staphylococcus aureus peptidoglycan. We considered that specific hyporesponsiveness in LPS-adapted My or in blood monocytes could be due to decreased expression of CD14 or diminished binding of LBP-LPS complexes to CD14. However, flow cytometry analysis revealed only minimal reduction of CD14 expression or CD14-dependent binding of a fluorescent LPS derivative when normo-and hyporesponsive cells were compared. These results show that complexes of LPS and LBP are more effective than LPS alone in inducing adaptation to LPS, and LPS-induced hyporesponsiveness probably results from changes in cellular elements distinct from CD14 that are involved in either LPS recognition or LPS-specific signal transduction. (J. Clin.
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