Hederasaponin C Alleviates Lipopolysaccharide-Induced Acute Lung Injury In Vivo and In Vitro Through the PIP2/NF-κB/NLRP3 Signaling Pathway

被引:30
作者
Han, Shan [1 ,2 ]
Yuan, Renyikun [2 ]
Cui, Yushun [1 ]
He, Jia [1 ,2 ]
Wang, Qin-Qin [1 ]
Zhuo, Youqiong [1 ]
Yang, Shilin [1 ,3 ]
Gao, Hongwei [1 ,3 ]
机构
[1] Guangxi Univ Chinese Med, Coll Pharm, Nanning, Peoples R China
[2] Jiangxi Univ Tradit Chinese Med, State Key Lab Innovat Drug & Efficient Energy Sav, Nanchang, Jiangxi, Peoples R China
[3] Guangxi Univ Chinese Med, Guangxi Engn Technol Res Ctr Adv Chinese Patent D, Nanning, Peoples R China
基金
中国国家自然科学基金;
关键词
acute lung injury; hederasaponin C; epigenetic; PIP2; NF-kappa B; NLRP3; inflammasome; NF-KAPPA-B; NLRP3; INFLAMMASOME; NADPH OXIDASE; KINASE; ACTIVATION; INHIBITION; TAK1; PATHOGENESIS; MECHANISMS; CELLS;
D O I
10.3389/fimmu.2022.846384
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Gene transcription is governed by epigenetic regulation that is essential for the pro-inflammatory mediators surge following pathological triggers. Acute lung injury (ALI) is driven by pro-inflammatory cytokines produced by the innate immune system, which involves the nod-like receptor 3 (NLRP3) inflammasome and nuclear factor-kappa B (NF-kappa B) pathways. These two pathways are interconnected and share a common inducer the phosphatidylinositol 4,5-bisphosphate (PIP2), an epigenetic regulator of (Ribosomal ribonucleic acid (rRNA) gene transcription, to regulate inflammation by the direct inhibition of NF-kappa B phosphorylation and NLRP3 inflammasome activation. Herein, we report that hederasaponin C (HSC) exerted a therapeutic effect against ALI through the regulation of the PIP2/NF-kappa B/NLRP3 signaling pathway. In lipopolysaccharide (LPS)/lipopolysaccharide + adenosine triphosphate (LPS+ATP)-stimulated macrophages, our results showed that HSC remarkably inhibited the secretion of interleukin-6 (IL-6), IL-1 beta, and tumor necrosis factor-alpha (TNF-alpha). Moreover, HSC inhibited NF-kappa B/p65 nuclear translocation and the binding of PIP2 to transforming growth factor-beta activated kinase 1 (TAK1). The intracellular calcium (Ca2+) level was decreased by HSC via the PIP2 signaling pathway, which subsequently inhibited the activation of NLRP3 inflammasome. HSC markedly alleviated LPS-induced ALI, restored lung function of mice, and rescued ALI-induced mice death. In addition, HSC significantly reduced the level of white blood cells (WBC), neutrophils, and lymphocytes, as well as pro-inflammatory mediators like IL-6, IL-1 beta, and TNF-alpha. Hematoxylin and eosin (H & E) staining results suggested HSC has a significant therapeutic effect on lung injury of mice. Interestingly, the PIP2/NF-kappa B/NLRP3 signaling pathway was further confirmed by the treatment of HSC with ALI, which is consistent with the treatment of HSC with LPS/LPS+ATP-stimulated macrophages. Overall, our findings revealed that HSC demonstrated significant anti-inflammatory activity through modulating the PIP2/NF-kappa B/NLRP3 axis in vitro and in vivo, suggesting that HSC is a potential therapeutic agent for the clinical treatment of ALI.
引用
收藏
页数:19
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