Bacterial endotoxins have been defined as integral components of the outer cell membrane of virtually all gram negative bacteria. When released from the organism during the course of bacterial infections, these potent bacterial products have an almost unlimited capacity to interact with mammalian cells and tissues. The consequences of these interactions may be extremely deleterious to the host and can result in fever, hypotension and disseminated intravascular coagulation. These characteristic manifestations of severe gram negative infections define a clinical state termed endotoxin shock. In this respect, endotoxin has been suggested to be one of the major contributing factors to the high incidence of mortality in gram negative bacteremia and sepsis, estimated to be as high as twenty thousand individuals annually in the United States alone. Intensive investigations during the past several decades have identified the lipopolysaccharide component of endotoxin, and more specifically the lipid A region of lipopolysaccharide, as an important biochemical element for the expression of endotoxin activity. However, the broad spectrum of biological activities of lipopolysaccharide/endotoxin has precluded a precise delineation of those interactions which are critical for manifestation of host tissue injury. In addition, in those cells which have been documented to recognize and respond to lipopolysaccharide, such as lymphocytes and macrophages, the mechanism by which these cells are triggered by lipopolysaccharide is completely unknown. Experiments outlined in this proposal have been designed to explore the concept of specific endotoxin receptors on the membranes of such cells. For these studies we will utilize extensively a mutant mouse strain, termed the C3H/HeJ strain, which is refractory to virtually all of the immunostimulatory and pathophysiologic effects of endotoxin, both in vitro and in vivo. The proposed research will employ both biochemical and immunologic techniques to define the molecular basis for endotoxin unresponsiveness of this C3H/HeJ mouse at the cellular level. These studies will contribute to our understanding of molecular interactions of endotoxin with mammalian cells.
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