静脉注射重组高密度脂蛋白可改善脓毒症小鼠的存活率

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Reconstituted High-density Lipoprotein Therapy Improves Survival in Mouse Models of Sepsis

背景与目的

高密度脂蛋白具有多种作用，包括抗炎、抗凋亡和脂多糖中和特性。本研究旨在评价静脉注射重组高密度脂蛋白(CSL-111)对不同脓毒症模型的影响。

方  法

将10周龄C57BL/6小鼠采用盲肠结扎穿孔或腹腔注射大肠杆菌或铜绿假单胞菌肺炎的方法建立脓毒症模型。脓毒症后2h给予CSL-111或生理盐水。主要观察指标为存活率。次要观察指标为浆细胞游离DNA和细胞因子浓度、组织学、细菌计数和生物分布。

结 果  

与生理盐水相比，CSL-111提高了盲肠结扎穿孔模型和腹腔模型小鼠的存活率(盲肠结扎穿孔模型16只小鼠中存活13只[存活率为81% ] vs. 生理盐水处理组16只小鼠存活6只[存活率为38%]，P=0.011；腹腔模型中10只小鼠存活4只[存活率为40%] vs. 生理盐水处理组10只小鼠存活0只[存活率为0%]，P=0.011)。与生理盐水组相比，CSL-111组中浆细胞游离DNA浓度较低(68 [24~123]pg/ml vs. 351 [333~683] pg/ml; P < 0.001)。注射CSL-111小鼠在盲肠结扎穿孔模型建立后24h，血浆(（200 [28~ 2302] vs. 2500 [953 ~3636] 菌落形成单位/ml；P = 0.021）和肝脏(1359 [360~1648] vs. 1808 [1464~2720] 菌落形成单位/ml; P = 0.031)中细菌计数均下降。在肺炎模型中，CSL-111组小鼠肝脏、肺内细菌积聚较少。CSL-111组小鼠肺组织炎症程度也明显低于生理盐水组(CD68+/总细胞比率：生理盐水组 0.24[0.22~0.27]；CSL-111组 0.07[0.01~0.09]；P<0.01)。在所有的模型中，细胞因子浓度无显著差异。铟-111细菌标记显示，上述结果可能与高密度脂蛋白摄入促进潜在的肝脏细菌清除有关。

结 论

CSL-111输注可提高不同脓毒症小鼠模型的存活率。它减少了血浆和器官的炎症，降低了细菌数量。这为探索高密度脂蛋白在感染性疾病中的治疗潜力提供了机会。

原始文献来源及摘要

Tanaka S,  Genève C,  Zappella N, et al. Reconstituted High-density Lipoprotein Therapy Improves Survival in Mouse Models of Sepsis[J]. Anesthesiology, 2020, 132:825-38.

Abstract

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 24h 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. 111Indium 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.

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文中所涉及药物使用、疾病诊疗等内容仅供参考。

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