Gram negative bacterial sepsis continues to be major cause of morbidity and mortality in the severely traumatized patient. It has been demonstrated that bacterial lipopolysaccharides (LPS) are capable of producing in the experimental host pathophysiologic changes which resemble those seen in the septic patient. Additionally, the hepatic macrophage (H-Mo) has been shown to be the major host site of localization for intravenously injected LPS. Since Mo are known to produce multiple potential mediators, the long-term goal of this proposal is to elucidate the contribution of the LPS:H-Mo interaction in LPS-induced shock and DIC. For these studies, rabbit H-Mo will be isolated from each of three experimental groups of animals: 1) untreated controls; 2) animals sensitized to LPS-induced toxicity; and 3) animal immunized (tolerant) to LPS-induces injury. Cytotoxicity will be followed by cellular viability and by the release of LDH and acid hydrolases from the explanted Mo. LPS produces a diffuse DIC in the experimental host and induces the production of a tissue factor procoagulant activity (PCA) in mononuclear phagocytes. In contracts, we have shown that LPS incudes in the H-Mo, a unique PCA with serine protease-like activity. In the proposed investigation, the chemical nature of this H-Mo PCA will be further evaluated and the inducibility of this PCA by LPS in H-Mo from the various experimental groups will be explored. Another consistent event in endotoxemia is hypotensive shock. Other Mo populations have been shown to produce large amounts of biological mediators derived from arachidonic acid (AA) in response to LPS stimulation. The specificity of the response, however, depends in part on the source of the Mo, and, present, the products of AA metabolism in the H-Mo are unknown. To explore the potential contribution of H-Mo to shock in endotoxemia, the ability of explanted H-Mo to produce prostanoids capable of producing vasodilation, increased vascular permeability andy hypotension will be evaluated in each of the three experimental groups. In addition, the effect of cyclooxygenase and lipoxygenase inhibitors on the ability to sensitize or induce tolerance to LPS will be studied.