Robustaflavone-4 '-dimethyl ether from Selaginella uncinata attenuated lipopolysaccharide-induced acute lung injury via inhibiting FLT3-mediated neutrophil activation
Robustaflavone-4 '-dimethyl ether from Selaginella uncinata attenuated lipopolysaccharide-induced acute lung injury via inhibiting FLT3-mediated neutrophil activation
复制标题
卷柏黄酮-4 '-二甲醚通过抑制FLT 3介导的中性粒细胞活化减轻脂多糖诱导的急性肺损伤
DOI：
10.1016/j.intimp.2020.106338
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发表时间：
2020
影响因子：
5.6
通讯作者：
Chen-Huan Yu
中科院分区：
文献类型：
--
作者：
Xiao-Ning Wu;Yang Yang;Huan-Huan Zhang;Yu-Sen Zhong;Fang Wu;Bing Yu;Chen-Huan Yu
中性粒细胞既是信使又是效应者，参与了急性肺损伤(ALI)的发病过程。靶向中性粒细胞可能是防治ALI的一种新策略。卷柏被广泛用作镇咳、解热和抗炎的草药，用于治疗各种肺部疾病，包括肺癌、哮喘、肺纤维化和肺炎。然而，其有效成分仍不清楚。本研究对黄酮类化合物的保护作用进行了研究。用小鼠和中性粒细胞研究了灯盏花素及其主要成分罗布斯塔夫酮-4‘-二甲基醚对脂多糖诱导的小鼠急性肺损伤的抑制作用，结果表明，灯盏花素和罗布斯塔夫酮对脂多糖诱导的小鼠急性肺损伤有相同的抑制作用，对中性粒细胞的浸润和肺水肿均有抑制作用，并能增加血清IL-6、肿瘤坏死因子-α、P-选择素和细胞间黏附分子-1的水平。此外，RDE以浓度依赖的方式显著抑制可诱导的中性粒细胞活化，并降低细胞内钙离子水平和CCR2的表达。救援实验表明，RDE抑制Flt3及其下游的p-p38和p-AKT，可被Flt3激动剂Flt3L所阻断，但可被MAPK激动剂PDBu或AKT激动剂SC79部分阻断。这些结果表明，RDE作为SUF中的主要生物活性成分，通过抑制Flt3介导的AKT和MAPK通路，减轻了内毒素诱导的急性肺损伤，并抑制了中性粒细胞的激活。
Neutrophils act as both messenger and effector which contributed to the pathogenesis of acute lung injury (ALI). Targeting neutrophils could be a novel strategy for prevention and treatment of ALI.Selaginella uncinatais widely used as an antitussive, antipyretic and anti-inflammatory herb to treat various pulmonary diseases, including lung cancer, asthma, pulmonary fibrosis and pneumonia. However, its effective constituents remain unknown. In the present study, the protective effects of flavonoids fromS. uncinata(SUF) and its major compound robustaflavone-4′-dimethyl ether (RDE) against lipopolysaccharide (LPS)-induced ALI were investigated in mice and in neutrophils. The results showed that both SUF and RDE had the same inhibition on LPS-induced lung edema and neutrophil infiltration as well as the increased levels of IL-6, TNF-α, P-selectin and ICAM-1 in serum of LPS-challenged mice. Furthermore, RDE significantly inhibited inducible neutrophil activation in a concentration-dependent manner, and also reduced the levels of intracellular calcium as well as the expressions of CCR2. Rescue experiment showed that RDE suppressed FLT3 and its downstream p-p38 and p-AKT, which could be abolished by FLT3 agonist FLT3L but partly by MAPK agonist PDBu or AKT agonist SC79. Therefore, these results indicated that RDE as the main bioactive compound in SUF alleviated LPS-induced acute lung injury and inhibited neutrophil activation via inhibition of FLT3-mediatied AKT and MAPK pathways.