| Sepsis has been redefined as " the systemic inflammatory response to infection" . Septic shock is that sepsis-induced hypotension persists despite adequate fluid resuscitation, along with the hypoperfusion and organ dysfunction, lactic acidosis, oliguria, or altered mental status are frequent manifestations of hypoperfusion. Septic shock is a highly complex pathophysiological state representing a major challenge to physicians. Despite aggressive treatment and increased understanding of the molecule aspects of septic shock, mortality in established septic shock is more than 50%. In the United States, septicemia is the 13th leading cause of death and causes more than 100 000 deaths per year. Experimental and clinical evidence have demonstrated that a variety of inflammatory response mediators, such as TNF-a, IL-1β, IL-6 and NO, are released by activated blood cells, vascular cells and different parenchyma! cells during sepsis. Regulation of the expression of these mediators is critical for normal homeostasis and host defence, whereas overexpression may result in tissue injury, multiple organ dysfunction and death. Laboratory studies have shown protection against experimentally induced sepsis through the use of agents that inhibit specific mediators in the cascade, including endotoxin, TNF-a and IL-1β. However, despite promising results in animal trial, clinical trials applying such specific ther-apies have been unable to duplicate the success seen in the laboratory, and have so far failed to show improved survival. Hence, these is a continuous search for new therapeutic options.The induction of tolerance to the systemic effects of endotoxin is a potential form of immunomodulatory therapy. A transient refractoriness to the effects of LPS known as endotoxin tolerance was encountered almost a century ago by physicians who employed bacterial vaccines for fever therapy, and first studied by Beeson, who observed a decrease in febrile response when rabbits were injected repeatedly with this compound. It is well recognized that when a health human (or experimental animal) is repeatedly injected intravenously with nonlethal doses of LPS, increasing resistance developes to its pyrogenic and subjective toxic effects. It is also known - in different animal models - that tolerance can be induced to its metabolic and lethal effects. LPS tolerance was not a permanent phenomenon, which was found to last 2 weeks in the rat. Based on studies in the rabbit, Greisman et al. suggested that LPS tolerance was controlled at the cellular level. In fact, adoptive transfer experiments have shown that LPS tolerance operates at the level of monocytes/macrophages. Consistant with this concept, multiple studies have demonstrated ex vivo tolerance of these cells; When, for instance, rabbits were repeatedly injected with LPS and their peritoneal macro-phages were harvested and stimulated with LPS in vitro, their TNF response was strongly decreased as compared to cells from nontolerant animals. A few problems have to be considered with these in vitro studies: Too short a primary culture may result in a hangover of response into the secondary culture. A proper dose of LPS in the primary culture is important, as very low dose may even result in an enhanced response. LPS contamination has to be excluded, since low amounts of contaminated LPS may induce tolerance already in the control cultures. Especially for primary cells, explanted from blood or tissue, the effects of culture adaption and in vitro maturation must be considered.Endotoxin tolerance can also be induced by using nontoxic derivatives of thelipid A component of the lipoplysacchride molecule. A number of these derivatives , such as monophosphoryl lipid A, retain the immunoadjuvant properties of lipopolysacchride, but are significantily less toxic than the parent molecule.Some experiments demonstrated that LPS pretreatment could attenuated en-dotoxemia, but the mechanism behind this effect is not well known. One possible hypothesis would be t...
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