Synthetic HDL_ a Potential Sepsis Therapy

High-density lipoprotein (HDL) is key a component of circulating blood and plays essential roles in vascular endothelial cells and immunity. However, the levels of HDL decrease by 50-70% in septic patients, which is associated with a poor prognosis. Using ApoA-I null mice as an HDL deficient model, we recently reported that mice lacking HDL are susceptible to cecal ligation and puncture (CLP)-induced septic death, and increase HDL levels by over expression of ApoA-I protects CLP-induced septic death. These clinical and animal studies indicate that a decrease in HDL levels is a risk factor for sepsis and raising circulating HDL levels may provide an efficient therapy for sepsis. In this application we demonstrated that sHDL treatment significantly protects mice from CLP-induced septic death, indicating that sHDL is a potential effective therapy for sepsis. We hypothesize that rHDL therapy protects sepsis by restoring both HDL level and its immune- and vascular-protective functions. The objective of this grant is to understand mechanism(s) of rHDL vascular protection, and to tailor the rHDL composition and treatment regimen specifically for sepsis. To achieve the grant objectives we plan to: 1) elucidate the mechanisms of rHDL protection against sepsis- induced vascular pathogenesis; 2) Tailor rHDL composition for increased efficacy in sepsis; and 3) Optimize rHDL treatment regimen for sepsis. Completion of this preclinical study will provide a body of mechanistic data for a novel sHDL-based therapeutic approach for treatment of sepsis and position it for rapid clinical translation.