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Background  It 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 (H 2 O 2 )-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 H 2 O 2 -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.    Methods  SAECs were pretreated with CAM (1, 5, and 10 μM) for 72 h, and subsequently exposed to H 2 O 2  (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.    Results  Pretreatment with low-dose (1 and 5 μM) CAM for 72 h inhibited H 2 O 2 -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.    Conclusions  CAM 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.    Electronic supplementary material  The online version of this article (10.1186/s40780-018-0120-4) contains supplementary material, which is available to authorized users.

journal of pharmaceutical health care and sciences

Low concentrations of clarithromycin upregulate cellular antioxidant enzymes and phosphorylation of extracellular signal-regulated kinase in human small airway epithelial cells