LPS EFFLUX HOST CELLS TO PLASMA LIPOPROTEINS

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Description (adapted from applicant's abstract): Bacterial lipopolysaccharides (LPS) are potent immunomodulatory compounds which, during the course of Gram negative infections, probably play a major role in the induction of septic shock. Therefore, a complete understanding of host mechanisms involved in the transport, detoxification, and attenuation of immune modulation by these potent bacterial membrane constituents will be necessary to formulate effective interventional strategies for septic shock. Previous work from several laboratories has shown that LPS released from the surface of Gram negative bacteria appear to have two fates: LPS may bind to leukocytes to initiate an inflammatory responses, or they made bind to plasma lipoproteins which attenuates LPS bioactivity and facilitates clearance. Recent work in Dr. Kitchens' laboratory suggests that there is an additional component in the host response to LPS. LPS may be removed from the surface of leukocytes and complexed with plasma lipoproteins or mixtures of purified high-density lipoproteins (HDL). This phenomenon is referred to as LPS efflux. The induction of acute phase reactants during inflammation may enhance LPS efflux. Finally, LPS efflux may be responsible for down-regulation of the host inflammatory response to LPS. Four specific aims are offered to address the hypothesis that LPS efflux reduces cellular responses to LPS. Specific aim 1: To determine the roles played by cell surface proteins in LPS traffic between cells and lipoproteins. Specific aim 2: To determine the roles played by soluble lipid transfer proteins in LPS efflux and in responses to cells that have acquired LPS. Specific aim 3: To evaluate the relative importance of natural lipoprotein classes from normal and acute phase plasma as acceptors for cell-associated LPS. Specific aim 4: To study the impact of LPS efflux on cellular responses to LPS.