Affiliation:
1. General Hospital of Ningxia Medical University
2. Guangzhou Medical University
3. The First Affiliated Hospital of Guangzhou Medical University
Abstract
Abstract
Hypoxia-inducible factor-1α (HIF-1α) plays an important regulatory role in inflammatory and hypoxic diseases. Higher HIF-1α level was found in 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. CS-exposed mice were intragastrically treated with different doses of digoxin(0.02mg/kg and 0.1mg/kg, once a day, and 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 S7959(100uM). Moreover, epithelial mesenchymal transition(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 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 was 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.
Publisher
Research Square Platform LLC
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