Sepsis is a major health issue with mortality exceeding 30% and few treatment options. We found that high-density lipoprotein cholesterol (HDL-C) abundance was reduced by 45% in septic patients compared to that in nonseptic patients. Furthermore, HDL-C abundance in nonsurviving septic patients was substantially lower than in those patients who survived. We therefore hypothesized that replenishing HDL might be a therapeutic approach for treating sepsis and found that supplementing HDL with synthetic HDL (sHDL) provided protection against sepsis in mice. In mice subjected to cecal ligation and puncture (CLP), infusing the sHDL ETC-642 increased plasma HDL-C amounts and improved the 7-day survival rate. Septic mice treated with sHDL showed improved kidney function and reduced inflammation, as indicated by marked decreases in the plasma concentrations of blood urea nitrogen (BUN) and the cytokines interleukin-6 (IL-6) and IL-10, respectively. We found that sHDL inhibited the ability of the endotoxins LPS and LPA to activate inflammatory pathways in RAW264.7 cells and HEK-Blue cells expressing the receptors TLR4 or TLR2 and NF-кB reporters. In addition, sHDL inhibited the activation of HUVECs by LPS, LTA, and TNF-α. Together, these data indicate that sHDL treatment protects mice from sepsis in multiple ways and that it might be an effective therapy for patients with sepsis.
|State||Published - Mar 15 2022|
Bibliographical noteFunding Information:
This publication was made possible by NIH R01GM113832 (to X.-A.L. and A.S.); NIH R01GM121796, NIH R35GM141478, and VA 1I01BX004639 (to X.-A.L.); AHA 13SDG17230049 (to A.S.); NIH T32-HL125242 (to E.E.M. and M.V.F.); T32 GM008353 (to E.M.); and T32 GM007767 (to M.V.F.). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS, NIH, VA, or AHA.
© 2022 The Authors, some rights reserved.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology