Abstract
BackgroundIt is well known that low-dose, long-term macrolide therapy is effective against chronic inflammatory airway diseases. Oxidative stress is considered to be a key pathogenesis factor in those diseases. However, the mechanism of action of low-dose, long-term macrolide therapy remains unclear. We have reported that clarithromycin (CAM), which is a representative macrolide antibiotic, could inhibit hydrogen peroxide (H2O2)-induced reduction of the glutathione (GSH)/glutathione disulfide (GSSG) ratio in human small airway epithelial cells (SAECs), via the maintenance of GSH levels through an effect on γ-glutamylcysteine synthetase (γ-GCS) expression. In this study, we examined the influence of CAM against H2O2-induced activities of cellular antioxidant enzymes and phosphorylated extracellular signal regulatory kinase (p-ERK) using SAECs, the main cells involved in chronic airway inflammatory diseases.MethodsSAECs were pretreated with CAM (1, 5, and 10 μM) for 72 h, and subsequently exposed to H2O2 (100 μM) for 0.5–2 h. Levels of GSH and GSSG, and activities of glutathione peroxidase (GPx)-1, glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), heme oxygenase (HO)-1 and p-ERK were assayed. mRNA expressions of GPx-1 and HO-1 were measured using the real-time reverse transcription polymerase chain reaction (RT-PCR). Tukey’s multiple comparison test was used for analysis of statistical significance.ResultsPretreatment with low-dose (1 and 5 μM) CAM for 72 h inhibited H2O2-induced reductions of GPx-1, GR, SOD, CAT and HO-1 activities, and mRNA expressions of GPx-1 and HO-1, and improved the GSH/GSSG ratio. However, these alterations were not observed after pretreatment with high-dose (10 μM) CAM, which suppressed phosphorylation of cell proliferation-associated ERK to cause a significant (p < 0.01) decrease in cell viability.ConclusionsCAM is efficacious against deterioration of cellular antioxidant enzyme activity caused by oxidative stress under low-dose, long-term treatment conditions. On the other hand, pretreatment with high-dose CAM suppressed phosphorylation of cell proliferation-associated ERK and decreased cell viability. The present study may provide additional evidence as to why low-dose, long-term administration of macrolides is effective for treating chronic inflammatory airway diseases.
Highlights
It is well known that low-dose, long-term macrolide therapy is effective against chronic inflammatory airway diseases
We examined the effect of CAM on Hydrogen peroxide (H2O2)-induced expression of glutathione peroxidase (GPx)-1, glutathione reductase (GR), superoxide dismutase (SOD), heme oxygenase (HO)-1 and CAT in Human small airway epithelial cell (SAEC) under the same conditions previously demonstrated to show the cytoprotective effect of Glutathione reductase (GR)
Effects of CAM pretreatment on the H2O2-induced GSH/Oxidized glutathione (GSSG) ratio in SAECs SAECs were pretreated with CAM at 1, 5 or 10 μM for 72 h
Summary
It is well known that low-dose, long-term macrolide therapy is effective against chronic inflammatory airway diseases. We examined the influence of CAM against H2O2-induced activities of cellular antioxidant enzymes and phosphorylated extracellular signal regulatory kinase (p-ERK) using SAECs, the main cells involved in chronic airway inflammatory diseases Macrolides such as clarithromycin (CAM) have been reported to be effective for the treatment of chronic inflammatory airway diseases at low doses and with long-term administration [1,2,3,4,5]. In chronic inflammatory respiratory diseases such as chronic obstructive pulmonary disease (COPD) [9], bronchial asthma [10], bronchiectasis [11] and cystic fibrosis [12], the H2O2 concentration in the exhaled breath has been reported to be several times higher than healthy subjects In these pathological conditions, it may be considered that the oxidant/antioxidant balance in bronchial epithelial cells is seriously impaired. This alteration was not observed after pretreatment with high-dose (10 μM) or short-term (24 and 48 h)
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