Abstract 159: Synthetic High Density Lipoprotein - a Potential Therapy for Sepsis
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Introduction: Sepsis is the leading cause of death in critically ill patients with mortality rates exceeding 30%. The ability of endogenous HDL to neutralize and facilitate elimination of lipopolysaccharides (LPS) is known and synthetic HDLs (sHDL) have been administered in sepsis models with varying success. In the current study we optimized composition of sHDL, apolipoprotein A-I (apoA-I) mimetic peptide-phospholipid particles, to maximize their protective effect against endothelial dysfunction in sepsis, and examined changes in HDL and apoA-I levels in patients with sepsis to select sHDL doses for evaluation in a sepsis animal model. Methods/Results: We first measured HDL cholesterol (HDL-C) and apoA-I in patients at time of intake to the intensive care unit, observing HDL to be 45% lower in septic patients compared to non-septic patients (p<0.01), with HDL levels in non-surviving septic patients being significantly lower compared to those in surviving septic patients (p<0.01). Next, we tested a new generation of sHDL, ETC642, for its efficacy on cecal ligation and puncture (CLP)-challenged mice. We administered sHDL to mice 2h post CLP and found that sHDL treatment significantly increased plasma HDL-C and decreased BUN, plasma IL-6 and IL-10 levels. More importantly, sHDL therapy improved 7d survival rate greater than 2-fold over PBS treated mice (p=0.01). To understand the mechanisms underlying sHDL protection, we investigated the effect of sHDL on endotoxin-induced inflammatory response in vitro . sHDL not only neutralized LPS/LTA but also suppressed TLR4-/TLR2-NF-kB signaling in macrophages, and inhibited LPS/LTA/TNF- induced endothelial cell activation. Conclusions: In this study, we show that HDL-C levels are markedly decreased in septic patients, which is associated with poor prognosis. We demonstrate that sHDL treatment increases HDL levels and effectively protects against CLP-induced septic death. We further established that sHDL therapy provides multiple protective mechanisms through LPS/LTA detoxification, suppressing inflammatory signaling in macrophages and inhibiting endothelial activation. Together, our findings suggest that targeting the vasculature via sHDL can be an effective platform for sepsis therapy.
