Abstract
BackgroundEotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways.MethodsAirway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1–20 μM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis.ResultsWhen airway epithelial cells were exposed to 2 μg/ml LPS, astragalin nontoxic at ≤20 μM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCβ2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin.ConclusionsAstragalin ameliorated oxidative stress-associated epithelial eosinophilia and apoptosis through disturbing TLR4-PKCβ2-NADPH oxidase-responsive signaling. Therefore, astragalin may be a potent agent antagonizing endotoxin-induced oxidative stress leading to airway dysfunction and inflammation.
Highlights
Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases
Suppression of LPS-promoted Toll-like receptor 4 (TLR4) induction by astragalin The TLR4 expression was very weak in untreated quiescent cells, whereas the TLR4 induction was greatly elevated in 2 μg/ml LPS-exposed BEAS-2B cells (Figure 1C)
The pinkish staining for the TLR4 induction was substantially and dose-dependently diminished in cells supplemented with astragalin (Figure 1D)
Summary
Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways. Bronchial epithelium is a key regulator of airway inflammation, airway wall remodeling and bronchial hyperresponsiveness in asthma, a complex immunologic and inflammatory disease [1]. The development of eosinophilic infiltration into the bronchial mucosa usually results in bronchial epithelial damage and airways hyperresponsiveness [6,7]. The bronchial epithelium is a target of inflammatory and physical insults as well as an effecter of ongoing airway inflammation. Eosinophilic inflammation might be associated with the pathophysiology of acute exacerbations of airway diseases. Defining the mechanisms that control recruitment of eosinophils into the airway epithelium can propose potential targets for novel therapy. The eosinophil recruitment in experimental airway diseases entails the binding of eotaxin to C-C chemokine receptor type 3 expressed on eosinophils, basophils and Th2 cells [8]
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