It is now appreciated that bacterial lipopolysaccharides (LPS) are responsible for initiating the pathophysiologic changes occurring in patients with gram-negative septicemia. The high mortality rate in this group of patients contributes to one of leading causes of death in the United States. The long range goal of this renewal proposal is to define the biochemical mechanisms of LPS interactions with key plasma proteins and tissue-fixed cells and to relate the interactions to the development of injury. The proposed studies will focus specifically on three areas: (i) studies of the mechanism of interaction of LPS with normal and acute phase serum paying particular attention to the regulation of LPS-high density lipoprotein (HDL) binding and to structure/function studies of the LPS-HDL complex, (ii) investigation of how cells recognize the presence of LPS by specifically characterizing the cell membrane components which interact with LPS and lead to cell activation, and (iii) characterization of the enzymatic mechanisms in the macrophage which lead to arachidonic acid release with specific emphasis on the isolation and characterization of phospholipases which catalyze arachidonic acid release from phospholipid. In addition to the relevance of the proposed studies to understanding the mechanism of action of LPS, these studies will provide more general information about the role of acute phase reactants in regulating the host response to inflammatory stimuli, about the molecular basis of the early steps of B-cell activation and about the properties of the phospholipases which may control the production of potent mediators (prostaglandins and leukotrienes) of injury in a wide variety of pathologic conditions.
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