Department of Emergency, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
Department of Emergency, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
Int J Biochem Cell Biol. 2020 Sep;126:105819. doi: 10.1016/j.biocel.2020.105819. Epub 2020 Aug 1.
In sepsis, the protection of the vascular endothelium is essential and the maintenance of its function is critical to prevent further deterioration. High-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P) is a bioactive lipid in plasma and its role in sepsis has not been extensively studied. This study aimed to investigate the effects of HDL-S1P on sepsis in cellular and animal models, as well as human plasma samples.
We established an animal model of sepsis with different severities achieved by caecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection, and then explored the relationship between HDL-S1P and lung endothelial dysfunction in vivo. To determine the effects of HDL-S1P in the pulmonary endothelium of septic rats, we then injected HDL-S1P into septic rats to find out if it can reduce the lung injury caused by sepsis. Further, we explored the mechanism in vitro by studying the role of S1P-specific receptor agonists and inhibitors in LPS-stimulated human umbilical vein endothelial cells. We also explored the relationship between plasma HDL-S1P content and sepsis severity in septic patients by analysing their plasma samples.
HDL-S1P concentrations in plasma were negatively correlated with endothelial functional damage in sepsis, both in the animal model and in the septic patients in our study. In vivo, HDL-S1P injection significantly reduced pulmonary oedema and endothelial leakage in septic rats. In vitro, cell experiments showed that HDL-S1P effectively protected the proliferation and migration abilities of endothelial cells, which could be partly explained by its biased activation of the S1P receptor 1.
Our study preliminary explored the function of HDL-S1P in sepsis in cellular and animal models, as well as human subjects. The results indicate HDL-S1P protected endothelial functions in septic patients. Thus, it has therapeutic potential and can be used for the clinical treatment of sepsis.
在脓毒症中，保护血管内皮至关重要，维持其功能对于防止病情进一步恶化至关重要。高密度脂蛋白（HDL）相关的鞘氨醇-1-磷酸（S1P）是血浆中的一种生物活性脂质，其在脓毒症中的作用尚未得到广泛研究。本研究旨在探讨 HDL-S1P 在细胞和动物模型以及人类血浆样本中对脓毒症的影响。
我们通过盲肠结扎和穿刺（CLP）和脂多糖（LPS）注射建立了不同严重程度的脓毒症动物模型，然后探讨了 HDL-S1P 与肺内皮功能障碍之间的关系。为了确定 HDL-S1P 在脓毒症大鼠肺内皮中的作用，我们向脓毒症大鼠注射 HDL-S1P，以观察其是否可以减轻脓毒症引起的肺损伤。此外，我们通过研究 S1P 特异性受体激动剂和抑制剂在 LPS 刺激的人脐静脉内皮细胞中的作用，在体外探讨了其机制。我们还通过分析脓毒症患者的血浆样本，探讨了血浆 HDL-S1P 含量与脓毒症严重程度之间的关系。
在本研究的动物模型和脓毒症患者中，血浆中 HDL-S1P 浓度与脓毒症时内皮功能损伤呈负相关。在体内，HDL-S1P 注射可显著减轻脓毒症大鼠的肺水肿和内皮渗漏。在体外，细胞实验表明 HDL-S1P 可有效保护内皮细胞的增殖和迁移能力，这部分可以通过其对 S1P 受体 1 的偏向性激活来解释。
本研究初步探讨了 HDL-S1P 在细胞和动物模型以及人类中的脓毒症中的作用。结果表明，HDL-S1P 可保护脓毒症患者的内皮功能。因此，它具有治疗潜力，可用于脓毒症的临床治疗。
