在脂多糖诱导的急性肺损伤小鼠模型中，刺芒柄花素通过抑制坏死性凋亡对炎症和氧化应激产生有益作用。
Beneficial effects of aloperine on inflammation and oxidative stress by suppressing necroptosis in lipopolysaccharide-induced acute lung injury mouse model.
作者信息
Cui Yan-Ru, Qu Fei, Zhong Wen-Jing, Yang Hui-Hui, Zeng Jie, Huang Jun-Hao, Liu Jie, Zhang Ming-Yue, Zhou Yong, Guan Cha-Xiang
机构信息
Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan 410078, China; Department of Physiology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China.
Department of Pharmacology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China.
出版信息
Phytomedicine. 2022 Jun;100:154074. doi: 10.1016/j.phymed.2022.154074. Epub 2022 Mar 27.
RATIONALE
Alveolar epithelial cell death, inflammation, and oxidative stress are typical features of acute lung injury (ALI). Aloperine (Alo), an alkaloid isolated from Sophora alopecuroides, has been reported to display various biological effects, such as anti-inflammatory, immunoregulatory, and anti-oxidant properties. In this study, we investigated the effects and mechanisms of Alo in treating a lipopolysaccharide (LPS)-induced ALI in a murine model.
METHODS
The effects of Alo in LPS-induced ALI were investigated in C57BL/6 mice. The RIPK1 inhibitor (Nec-1) and the RIPK3 inhibitor (GSK'872) were used to evaluate the relationship of necroptosis, NF-κB activation, and PDC subunits in LPS-treated mouse alveolar epithelial cells (MLE-12). Then the effects of Alo on necroptosis, inflammation, and oxidative stress of LPS-stimulated MLE-12 cells were evaluated.
RESULTS
Alo significantly attenuated histopathological lung injuries and reduced lung wet/dry ratio in LPS-induced ALI mice. Alo also remarkedly reduced total protein and neutrophils recruitment in bronchoalveolar lavage fluid of ALI mice. Meanwhile, Alo ameliorated the LPS-induced necroptosis in the lungs of ALI mice. The RIPK3 inhibitor GSK'872, but not the RIPK1 inhibitor Nec-1, reversed LPS-induced p65 phosphorylation and translocation to the nucleus in MLE-12 cells. GSK'872 also reversed the LPS-induced increase in ROS and binding of RIPK3 and PDC subunits in MLE-12 cells. Moreover, Alo down-regulated the levels of p-RIPK1, p-RIPK3, p-MLKL, p-p65, the translocation of p65 to the nucleus, and reduced the expression of IL-6 and IL-8 in LPS-stimulated MLE-12 cells. Alo also inhibited the binding of RIPK3 and PDC-E1α, PDC-E1β, PDC-E2, and PDC-E3 and the ROS production in LPS-treated MLE-12 cells.
CONCLUSION
The present study validated the beneficial effects of Alo on LPS-induced ALI , suggesting Alo may be a new drug candidate against ALI.
理论依据
肺泡上皮细胞死亡、炎症和氧化应激是急性肺损伤（ALI）的典型特征。从苦豆子中分离出的生物碱氧化槐果碱（Alo）已被报道具有多种生物学效应，如抗炎、免疫调节和抗氧化特性。在本研究中，我们研究了Alo在小鼠模型中治疗脂多糖（LPS）诱导的ALI的效果及机制。
方法
在C57BL/6小鼠中研究Alo对LPS诱导的ALI的作用。使用RIPK1抑制剂（Nec-1）和RIPK3抑制剂（GSK'872）来评估坏死性凋亡、NF-κB激活和PDC亚基在LPS处理的小鼠肺泡上皮细胞（MLE-12）中的关系。然后评估Alo对LPS刺激的MLE-12细胞坏死性凋亡、炎症和氧化应激的影响。
结果
Alo显著减轻了LPS诱导的ALI小鼠的组织病理学肺损伤，并降低了肺湿/干比。Alo还显著降低了ALI小鼠支气管肺泡灌洗液中的总蛋白和中性粒细胞募集。同时，Alo改善了ALI小鼠肺中LPS诱导的坏死性凋亡。RIPK3抑制剂GSK'872而非RIPK1抑制剂Nec-1逆转了LPS诱导的MLE-12细胞中p65磷酸化和向细胞核的转位。GSK'872还逆转了LPS诱导的MLE-12细胞中ROS增加以及RIPK3与PDC亚基的结合。此外，Alo下调了LPS刺激的MLE-12细胞中p-RIPK1、p-RIPK3、p-MLKL、p-p65的水平、p65向细胞核的转位，并降低了IL-6和IL-8的表达。Alo还抑制了LPS处理的MLE-12细胞中RIPK3与PDC-E1α、PDC-E1β、PDC-E2和PDC-E3的结合以及ROS的产生。
结论
本研究验证了Alo对LPS诱导的ALI的有益作用，表明Alo可能是一种抗ALI的新药候选物。
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