ENDOTOXIN TOLERANCE AFTER SEVERE INJURY AND ITS REGULATORY MECHANISMS

Objective: To study the responsiveness of peripheral blood mononuclear cells to lipopolysaccharide (LPS) after severe trauma and its regulat ory mechanisms. Materials and Methods: The release of proinflammatory reacting cytokines (tumor necrosis factor-alpha, interleukin (IL)-1 be ta, IL-6, IL-8, interferon (IFN)-gamma) into whole blood from 12 patie nts on day 1, 5, 10, and 14 after severe trauma (Injury Severity; Scor e, 39.3 +/- 2.8 points) and 10 healthy volunteers was studied after st imulation with LPS, concanavalin A, phorbol myristate acetate (PMA), a nd the addition of recombinant IFN-gamma. Main Results: Trauma caused a significant reduction of LPS and concanavalin A induced release of i nflammation activating cytokines into whole blood, including IFN-gamma . However, the diminished release of proinflammatory cytokines could b e increased with recombinant IFN-gamma or even attenuated after stimul ation of peripheral blood mononuclear cells with the protein kinase C activator PMA. Conclusions: Trauma leads to reduced responsiveness of blood monocytes to LPS and a decreased secretion of proinflammatory re acting lymphokines. Because activation of the protein kinase C pathway with PMA or the addition of IFN-gamma significantly increased cytokin e response, endotoxin tolerance is not caused by inhibition of protein synthesis, hut to disturbances in the signal transduction pathway and its regulating mediators.