Long-acting β2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages

Background: Treatment of COPD with a combination of long-acting beta(2) agonists and corticosteroids is currently used worldwide. The mechanisms of the anti-inflammatory effects and their associations with histone deacetylase (HDAC) activity remain unclear. Methods: Human alveolar macrophages were isolated and stimulated with H2O2 in the presence of varying concentrations of long-acting beta(2) agonists and corticosteroids. Supernatants were collected for IL-8 and MMP-9 measurements. Cell lysates were analyzed for HDAC (mainly HDAC1/HDAC2) activity. Quantitative real-time PCR was performed to determine the levels of IL-8 and MMP-9 mRNA. Results: Both long-acting beta(2) agonists, salmeterol and formoterol, and corticosteroids, fluticasone and budesonide, showed anti-inflammatory effects to a certain extent on H2O2-induced IL-8 and MMP-9 release in alveolar macrophages. Combinations of long-acting beta(2) agonists and corticosteroids exerted greater effects to suppress mediator release, and both transcription and translation of IL-8 and MMP-9 were inhibited. It seemed that the levels of IL-8 and MMP-9 after H2O2 stimulation were inversely associated with the activity of HDAC. H2O2 stimulation resulted in a significant decrease in HDAC activity and was associated with an increase in mediator release. In contrast, treatment with long-acting beta(2) agonists, corticosteroids or theophylline restored the H2O2-induced decrease in HDAC activity and inhibited mediator release. Conclusion: Combinations of long-acting beta(2) agonists and corticosteroids exerted greater effects on the suppression of mediator release in relation to the enhancement of HDAC activity. This supports at least in part the likely contribution of anti-inflammatory effects of long-acting beta(2) agonists and corticosteroids to the clinical benefits seen in COPD patients. (C) 2012 Elsevier Ltd. All rights reserved.