Abstract
BackgroundChronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema.MethodsMice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages.ResultsQuercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls. Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation. Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype.ConclusionsQuercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation
The volume-pressure curve was shifted further to the left, indicating further progression of emphysema after cessation of exposure to elastase/ LPS. This shift may be due to persistence of oxidative stress and matrix metalloproteinase (MMP) activity even after cessation of exposure to elastase/LPS
These data suggest that quercetin treatment prevented further progression of emphysema after elastase/LPS treatment rather than stimulating the regeneration of degraded alveoli
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by small airway inflammation/fibrosis, mucus plugging and emphysema. Inhalation of cigarette smoke and other environmental exposures can stimulate resident alveolar macrophages and lung epithelial cells to generate reactive oxygen species (ROS) and reactive nitric oxide species (RNS) in excess, thereby disturbing the oxidant to antioxidant balance, resulting in oxidative stress [2,3,4]. Chronic inflammation causes remodeling of the airways, including goblet cell metaplasia, mucus plugging and airway wall thickening
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