State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, PR China.
State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, PR China.
Biomed Pharmacother. 2020 May;125:109868. doi: 10.1016/j.biopha.2020.109868. Epub 2020 Feb 6.
Acute lung injury (ALI) or its most advanced form, acute respiratory distress syndrome (ARDS) is a severe inflammatory pulmonary process triggered by varieties of pathophysiological factors, among which apoptosis of pulmonary endothelial cells plays a critical role in the progression of ALI/ARDS. Ruscogenin (RUS) has been found to exert significant protective effect on ALI induced by lipopolysaccharides (LPS), but there is little information about its role in LPS-induced pulmonary endothelial cell apoptosis. The aim of the present study was to investigate the underlying mechanism in which RUS attenuates LPS-induced pulmonary endothelial cell apoptosis. Mice were challenged with LPS (5 mg/kg) by intratracheal instillation for 24 h to induce apoptosis of pulmonary endothelial cells in model group. RUS (three doses: 0.1, 0.3, and 1 mg/kg) was administrated orally 1 h prior to LPS challenge. The results showed that RUS could attenuate LPS-induced lung injury and pulmonary endothelial apoptosis significantly. And we observed that RUS inhibited the activation of TLR4/MYD88/NF-κB pathway in pulmonary endothelium after LPS treatment. In murine lung vascular endothelial cells (MLECs) we further confirmed that RUS (1 μmol/L) markedly ameliorated MLECs apoptosis by suppressing TLR4 signaling. By using TLR4 knockout mice we found that TLR4 was essential for the RUS-mediated eff ;ect on LPS-stimulated pulmonary endothelial apoptosis. Collectively, our results indicate that RUS plays a protective role against LPS-induced endothelial cell apoptosis via regulating TLR4 signaling, and may be a promising agent in the management of ALI.
急性肺损伤（ALI）或其最严重的形式，急性呼吸窘迫综合征（ARDS），是由多种病理生理因素触发的严重炎症性肺过程，其中肺内皮细胞凋亡在 ALI/ARDS 的进展中起着关键作用。鲁斯可醇（RUS）已被发现对脂多糖（LPS）诱导的 ALI 具有显著的保护作用，但关于其在 LPS 诱导的肺内皮细胞凋亡中的作用的信息很少。本研究旨在探讨 RUS 减轻 LPS 诱导的肺内皮细胞凋亡的潜在机制。通过气管内滴注 LPS（5mg/kg），在模型组中诱导 24 小时的肺内皮细胞凋亡。在 LPS 攻击前 1 小时，通过口服给予 RUS（三个剂量：0.1、0.3 和 1mg/kg）。结果表明，RUS 能显著减轻 LPS 诱导的肺损伤和肺内皮细胞凋亡。我们还观察到，RUS 抑制了 LPS 处理后肺内皮细胞 TLR4/MYD88/NF-κB 通路的激活。在鼠肺血管内皮细胞（MLECs）中，我们进一步证实，RUS（1μmol/L）通过抑制 TLR4 信号通路显著改善 MLECs 凋亡。通过使用 TLR4 敲除小鼠，我们发现 TLR4 对于 RUS 介导的 LPS 刺激的肺内皮细胞凋亡的影响是必需的。总之，我们的研究结果表明，RUS 通过调节 TLR4 信号通路，在 LPS 诱导的内皮细胞凋亡中发挥保护作用，可能是治疗 ALI 的一种有前途的药物。
