Niclosamide Ethanolamine Salt Alleviates Idiopathic Pulmonary Fibrosis by Modulating the PI3K-mTORC1 Pathway.
Niclosamide Ethanolamine Salt Alleviates Idiopathic Pulmonary Fibrosis by Modulating the PI3K-mTORC1 Pathway.
复制标题
氯硝柳胺乙醇胺盐通过调节 PI3K-mTORC1 通路减轻特发性肺纤维化
作者：
Pei X;Zheng F;Li Y;Lin Z;Han X;Feng Y;Tian Z;Ren D;Cao K;Li C
特发性肺纤维化(IPF)是一种以慢性进行性纤维化为特征的间质性肺炎，最终导致呼吸衰竭和早期死亡。尽管尚未被充分研究，但IPF发病的主要原因是成纤维细胞增殖异常和肺成纤维细胞分化而来的肌成纤维细胞过度沉积细胞外基质。更多的信号通路，包括PI3K-Akt-mTOR和自噬通路，参与了IPF的发病。氯硝柳胺乙醇胺盐(NEN)是抗肿瘤研究中报道的一种高效的多靶点小分子抑制剂。在这里，我们报告了在IPF动物模型中使用NEN治疗14天，观察到有诱人的肺功能和羟脯氨酸含量的缓解。为进一步探讨NEN对肺间质纤维化的治疗作用及对博莱霉素攻击小鼠肺切片的病理改变。此外，我们还研究了NEN对转化生长因子-β-1刺激的肺泡巨噬细胞系A549细胞的异常增殖和细胞外基质产生的影响。在非临床研究中，NEN可改善博莱霉素攻击小鼠的肺功能和组织病理学改变，并显著降低肺组织羟脯氨酸含量。在体外，NEN抑制PI3K-mTORC1信号，并阻止细胞周期，以防止成纤维细胞的不受控制的增殖。此外，NEN通过mTORC14EBP1轴抑制转化生长因子-β1诱导的上皮-间充质转化和细胞外基质聚集。此外，NEN激活的非典型自噬使成纤维细胞对凋亡重新敏感。以上结果表明，NEN可能通过调节PI3K-mTORC1和自噬途径发挥抗肝纤维化作用。这些数据为NEN在IPF中的治疗作用提供了强有力的证据。
Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia characterized by chronic progressive fibrosis, ultimately leading to respiratory failure and early mortality. Although not fully explored, the major causative factors in IPF pathogenesis are dysregulated fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) deposited by myofibroblasts differentiated from pulmonary fibroblasts. More signalling pathways, including the PI3K-Akt-mTOR and autophagy pathways, are involved in IPF pathogenesis. Niclosamide ethanolamine salt (NEN) is a highly effective multitarget small-molecule inhibitor reported in antitumor studies. Here, we reported that in an IPF animal model treated with NEN for 14 days, attractive relief of pulmonary function and hydroxyproline content were observed. To further explore, the therapeutic effect of NEN in IPF and pathological changes in bleomycin-challenged mouse lung sections were assessed. Additionally, the effects of NEN on abnormal proliferation and ECM production in IPF cell models established with TGF-β1-stimulated A549 cells or DHLF-IPF cells were studied. In nonclinical studies, NEN ameliorated lung function and histopathological changes in bleomycin-challenged mice, and the lung hydroxyproline content was significantly diminished with NEN treatment. In vitro, NEN inhibited PI3K-mTORC1 signalling and arrested the cell cycle to prevent uncontrolled fibroblast proliferation. Additionally, NEN inhibited TGF-β1-induced epithelial–mesenchymal transition (EMT) and ECM accumulation via the mTORC1-4EBP1 axis. Furthermore, NEN-activated noncanonical autophagy resensitized fibroblasts to apoptosis. The above findings demonstrated the potential antifibrotic effect of NEN mediated via modulation of the PI3K-mTORC1 and autophagy pathways. These data provide strong evidence for a therapeutic role for NEN in IPF.
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影响因子：
4.8
作者：
Chen W;Mook RA Jr;Premont RT;Wang J
通讯作者：
Wang J
吡非尼酮和尼达尼布对特发性肺纤维化患者全身氧化应激和炎症标志物的影响：初步报告。
DOI：
10.3390/antiox9111064
发表时间：
2020-10-30
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Fois AG;Sotgiu E;Scano V;Negri S;Mellino S;Zinellu E;Pirina P;Pintus G;Carru C;Mangoni AA;Zinellu A
通讯作者：
Zinellu A
DOI：
10.18502/ijaai.v19i4.4110
发表时间：
2020-08-25
期刊：
Iranian journal of allergy, asthma, and immunology
影响因子：
--
作者：
El-Baz LMF;Shoukry NM;Hafez HS;Guzy RD;Salem ML
通讯作者：
Salem ML
影响因子：
6
作者：
Cui, Yingying;Zhang, Mengfan;Faber, Klaas Nico
通讯作者：
Faber, Klaas Nico
影响因子：
6.1
作者：
Boyapally, Raju;Pulivendala, Gauthami;Godugu, Chandraiah
通讯作者：
Godugu, Chandraiah