From 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.).
Anesthesiology. 2020 Apr;132(4):825-838. doi: 10.1097/ALN.0000000000003155.
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.
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.
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.
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.
高密度脂蛋白具有多种作用，包括抗炎、抗凋亡和中和脂多糖的特性。作者评估了重组成分高密度脂蛋白（CSL-111）在不同脓毒症模型中的静脉注射效果。
10 周龄 C57BL/6 小鼠通过盲肠结扎和穿刺或腹腔内注射大肠埃希菌或铜绿假单胞菌肺炎引发脓毒症。在脓毒症后 2 小时给予 CSL-111 或生理盐水治疗。主要结局为存活率。次要结局为血浆无细胞 DNA 和细胞因子浓度、组织学、细菌计数和生物分布。
与生理盐水相比，CSL-111 改善了盲肠结扎和穿刺以及腹腔模型中的存活率（盲肠结扎和穿刺模型中 16 只中有 13 只[81%]存活，而盲肠结扎和穿刺模型中为 6 只[38%]；P=0.011；腹腔模型中 10 只中有 4 只[40%]存活，而腹腔模型中为 0 只[0%]；P=0.011）。CSL-111 组的无细胞 DNA 浓度低于生理盐水组（68[24 至 123]pg/ml 比 351[333 至 683]pg/ml；P<0.001）。在盲肠结扎和穿刺模型中，CSL-111 组在 24 小时时血浆（200[28 至 2,302]与 2,500[953 至 3,636]cfu/ml；P=0.021）和肝脏（1,359[360 至 1,648]与 1,808[1,464 至 2,720]cfu/ml；P=0.031）中的细菌计数均较低。在肺炎模型中，CSL-111 组的肝脏和肺部细菌积累较少。与生理盐水组相比，CSL-111 组的肺部炎症也较少（CD68+细胞与总细胞的比值：生理盐水组为 0.24[0.22 至 0.27]；CSL-111 组为 0.07[0.01 至 0.09]；P<0.01）。在所有模型中，细胞因子浓度均无差异。铟细菌标记强调了高密度脂蛋白摄取可能促进的肝脏细菌清除。
CSL-111 输注可提高不同脓毒症实验小鼠模型的存活率。它降低了血浆和器官中的炎症反应，并减少了细菌计数。这些结果强调了高密度脂蛋白在血管内皮和器官保护以及脂多糖/细菌清除中的关键作用。这表明有机会探索在脓毒症条件下使用高密度脂蛋白的治疗潜力。
