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Reconstituted High-density Lipoprotein Therapy Improves Survival in Mouse Models of Sepsis
Sébastien Tanaka1, Claire Genève, Nathalie Zappella
1From Réunion Island University, French Institute of Health and Medical Research (INSERM) U1188, Diabetes atherothrombosis Réunion Indian Ocean (DéTROI), CYROI Plateform, Saint-Denis de La Réunion, France (S.T., J.Y-S., C.P., M.B., D.C., O.M.) Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Anesthesiology and Critical Care Medicine, Bichat-Claude Bernard Hospital, Paris, France (S.T., C.G., N.Z., P.M.) INSERM U1148, Laboratory for Vascular Translational Science, Paris France (C.G., N.Z., L.L.) Réunion Island University, INSERM U1187, CNRS (National Center for Scientific Research) 9192, IRD (Institute for Research and Development) 249, PIMIT Laboratory, Infectious Processes in Tropical Island Environment, CYROI Plateform 2, Saint-Denis de La Réunion, France (W.V.) INSERM U1152, Physiopathology and Epidemiology of Respiratory Diseases, Paris, France (P.M.) INSERM U1137, Infection, Antimicrobials, Modelling, Evolution, Paris, France (E.D.) AP-HP, Department of Anesthesiology and Critical Care Medicine, Paris-Sud Hospitals, Paris-Sud University, Bicêtre Hospital, Le Kremlin-Bicêtre, France (J.D.) Clinical Research Unit (Bio-CANVAS: biomarkers in CardioNeuroVascular DISEASES) U942, Paris, France (J.D.) Réunion Island University-affiliated Hospital, France (D.C., O.M.).
Background:
High-density lipoproteins exert pleiotropic effects including antiinflammatory, antiapoptotic, and lipopolysaccharide-neutralizing properties. The authors assessed the effects of reconstituted high-density lipoproteins (CSL-111) intravenous injection in different models of sepsis.
Methods:
Ten-week-old C57BL/6 mice were subjected to sepsis by cecal ligation and puncture or intraperitoneal injection of Escherichia coli or Pseudomonas aeruginosa pneumonia. CSL-111 or saline solution was administrated 2 h after the sepsis. Primary outcome was survival. Secondary outcomes were plasma cell-free DNA and cytokine concentrations, histology, bacterial count, and biodistribution.
Results:
Compared with saline, CSL-111 improved survival in cecal ligation and puncture and intraperitoneal models (13 of 16 [81%] survival rate vs. 6 of 16 [38%] in the cecal ligation and puncture model; P = 0.011; 4 of 10 [40%] vs. 0 of 10 [0%] in the intraperitoneal model; P = 0.011). Cell-free DNA concentration was lower in CSL-111 relative to saline groups (68 [24 to 123] pg/ml vs. 351 [333 to 683] pg/ml; P < 0.001). Mice injected with CSL-111 presented a decreased bacterial count at 24 h after the cecal ligation and puncture model both in plasma (200 [28 to 2,302] vs. 2,500 [953 to 3,636] colony-forming unit/ml; P = 0.021) and in the liver (1,359 [360 to 1,648] vs. 1,808 [1,464 to 2,720] colony-forming unit/ml; P = 0.031). In the pneumonia model, fewer bacteria accumulated in liver and lung of the CSL-111 group. CSL-111-injected mice had also less lung inflammation versus saline mice (CD68+ to total cells ratio: saline, 0.24 [0.22 to 0.27]; CSL-111, 0.07 [0.01 to 0.09]; P < 0.01). In all models, no difference was found for cytokine concentration. Indium bacterial labeling underlined a potential hepatic bacterial clearance possibly promoted by high-density lipoprotein uptake.
Conclusions:
CSL-111 infusion improved survival in different experimental mouse models of sepsis. It reduced inflammation in both plasma and organs and decreased bacterial count. These results emphasized the key role for high-density lipoproteins in endothelial and organ protection, but also in lipopolysaccharide/bacteria clearance. This suggests an opportunity to explore the therapeutic potential of high-density lipoproteins in septic conditions.
