Zhang Kedong, Zhou Feng, Zhu Caixia, Yuan Liang, Li Defu, Wang Jian, Lu Wenju
Department of Pulmonary and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xian, Shaanxi, People's Republic of China.
Int J Chron Obstruct Pulmon Dis. 2025 May 23;20:1665-1678. doi: 10.2147/COPD.S493856. eCollection 2025.
Hypoxia-inducible factor-1α (HIF-1α) plays an important regulatory role in inflammatory and hypoxic diseases. Higher HIF-1α level was found in the lungs of chronic obstructive pulmonary disease (COPD) patients, however, its role in cigarette smoke (CS)-induced COPD has not been fully studied. Digoxin has been showed to inhibit HIF-1α translation and block HIF-1α activity and thus is often used as the HIF-1α inhibitor. Therefore, in the present study, we chose digoxin as the inhibitor to investigate whether HIF-1α contributes to the progression in a mouse model of COPD and possible mechanism.
The COPD model was established by cigarette smoke (CS) exposed; animals were intragastrically treated with vehicle or different doses of digoxin (0.02 mg/kg and 0.1 mg/kg). COPD associated phenotypes such as pathological changes in lungs, inflammation, lung function and mucus secretion in airways were evaluated. Meanwhile, cigarette smoke extract (CSE) treated A549 cells were administrated with digoxin (50nM) or Smad3 inhibitor (S7959 100uM). Moreover, EMT associated markers together with HIF-1α/TGF-β1/Smad3 signaling pathway were detected both in vivo and in vitro.
The level of HIF-1α was significantly increased in lungs of COPD mice and CSE-exposed A549 cells, which was markedly suppressed by digoxin. Moreover, digoxin inhibited CS-induced inflammatory responses, lung function decline, and mucus hyper-secretion in COPD mouse model. In vitro studies, digoxin decreased CSE-induced pro-inflammatory cytokine release. Importantly, CS-induced or CSE-induced EMT and up-regulation of HIF-1α/TGF-β1/Smad pathway were inhibited by digoxin in vitro. Additionally, S7959 mitigated CSE-induced EMT in A549 cells.
Digoxin can protect CS-induced COPD and prevent CS-induced EMT possibly through HIF-1α/TGF-β1/Smad3 signaling pathway in mice. This study suggests HIF1-α could be a potential intervention target for COPD prevention and treatment, especially for EMT in CS-induced COPD.
缺氧诱导因子-1α（HIF-1α）在炎症性疾病和缺氧性疾病中发挥重要的调节作用。在慢性阻塞性肺疾病（COPD）患者的肺组织中发现HIF-1α水平较高，然而，其在香烟烟雾（CS）诱导的COPD中的作用尚未得到充分研究。地高辛已被证明可抑制HIF-1α的翻译并阻断HIF-1α的活性，因此常被用作HIF-1α抑制剂。因此，在本研究中，我们选择地高辛作为抑制剂，以研究HIF-1α是否在COPD小鼠模型的病情进展中发挥作用及其可能的机制。
通过暴露于香烟烟雾（CS）建立COPD模型；动物经灌胃给予赋形剂或不同剂量的地高辛（0.02mg/kg和0.1mg/kg）。评估COPD相关表型，如肺部病理变化、炎症、肺功能和气道黏液分泌。同时，用香烟烟雾提取物（CSE）处理A549细胞，并给予地高辛（50nM）或Smad3抑制剂（S7959，100μM）。此外，在体内和体外检测与上皮-间质转化（EMT）相关的标志物以及HIF-1α/TGF-β1/Smad3信号通路。
COPD小鼠肺组织和CSE处理的A549细胞中HIF-1α水平显著升高，地高辛可明显抑制其升高。此外，地高辛抑制COPD小鼠模型中CS诱导的炎症反应、肺功能下降和黏液分泌过多。体外研究表明，地高辛可减少CSE诱导的促炎细胞因子释放。重要的是，地高辛在体外抑制了CS诱导或CSE诱导的EMT以及HIF-1α/TGF-β1/Smad通路的上调。此外，S7959减轻了CSE诱导的A549细胞中的EMT。
地高辛可能通过HIF-1α/TGF-β1/Smad3信号通路保护小鼠免受CS诱导的COPD，并预防CS诱导的EMT。本研究表明HIF1-α可能是COPD预防和治疗的潜在干预靶点，尤其是对于CS诱导的COPD中的EMT。
