AMELIORATION OF SEPSIS BY MACROPHAGE ACTIVATION

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Sepsis syndrome and septic shock are significant causes of morbidity and mortality in critically ill patients. Despite technological and therapeutic advances in critical care, sepsis continues to be a pivotal factor in 40% to 60% of deaths in surgical intensive care units. Sepsis syndrome occurs in 500,000 patients per year and is the 13th most common cause of death in the United States, resulting in an estimated 100,000 deaths per year. Unfortunately, the incidence of sepsis syndrome appears to be increasing nationwide. It is clear that alternative approaches to the prevention and/or management of sepsis must be found. Recent clinical studies indicate that macrophage activation with (1->3)-beta-D-glucans will significantly reduce septic morbidity and mortality in surgical patients. Our preliminary studies indicate that the antisepsis efficacy of glucans can be enhanced by altering the higher structure (i.e. branching frequency and degree of polymerization) of the molecule. The research outlined in this proposal will address two critical questions. I. Is there a molecular conformation of(1->3)-beta-D-glucan that will exert optimal anti-sepsis efficacy? II. What are the cellular and molecular mechanisms associated with glucan induced protection against sepsis? We will employ the murine cecal-ligation and puncture (CLP) model of septicemia and septic shock. To identify the (1->3)-beta-D-glucan polymer with the most significant anti-sepsis activity, we will conduct structure/activity relationship studies to determine whether altering the molecular conformation, side-chain branching frequency and/or polymer size will enhance anti-sepsis efficacy in the murine CLP model. When the (1->3)- beta-D-glucan that exerts optimal anti-sepsis activity has been identified, we will develop a molecular model of the polymer. We will examine the cellular and molecular mechanisms of (1->3)-beta-D-glucan in sepsis by determining; i) whether glucan binding to macrophages involves a specific receptor and the effect of sepsis on glucan-macrophage receptor binding; and ii) the effect of glucan and/or sepsis on macrophage signal transduction pathways. In addition, we will compare and contrast systemic and macrophage TNFalpha, IL-1beta, IL-6 and nitric oxide levels in the presence and absence of glucan and sepsis. We will also compare and contrast macrophage TNFalpha, IL-1beta, IL-6, IL-8 and inducible nitric oxide synthase gene transcription, translation and elaboration in the presence and absence of glucan and sepsis. Special emphasis will be placed on examination of TNFalpha, since glucans may inhibit the development of septic sequelae by down-regulating macrophage TNFalpha release. The long- range goal of this research is to understand the mechanism(s) by which glucans ameliorate sepsis and septic shock. These data may ultimately lead to the development of better management strategies for patients predisposed to sepsis and septic shock.