HIF-1α Contributes to the Progression of Chronic Obstructive Pulmonary Disease

Abstract

BackgroundHypoxia-inducible factor-1 (HIF-1) plays an important regulatory role in inflammatory and hypoxic diseases. Higher HIF-1 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-1 translation and block HIF-1 activity and thus is often used as the HIF-1 inhibitor. Therefore, in the present study, we chose digoxin as the inhibitor to investigate whether HIF-1 contributes to the progression of COPD and possible mechanism. MethodsCS-exposed mice were intragastrically treated with different doses of digoxin, and COPD-associated phenotypes such as pathological changes in lungs, inflammation, lung function and mucus secretion in airways were evaluated. Meanwhile, CSE-treated A549 cells were administrated with digoxin or S7959. Moreover, EMT-associated markers together with HIF-1\TGF-{beta}1\Smad3 signaling pathway were detected both in vivo and in vitro. ResultsThe level of HIF-1 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-1/TGF-{beta}1/Smad pathway was inhibited by digoxin. Additionally, S7959 mitigated CSE-induced EMT in A549 cells. ConclusionsDigoxin can protect CS-induced COPD and prevent CS-induced EMT possibly through HIF-1/TGF-{beta}1/Smad3 signaling pathway. This study suggests HIF1- could be a potential intervention target for COPD prevention and treatment, especially for EMT in CS-induced COPD.