Combination of erythromycin and dexamethasone improves corticosteroid

23 Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a 24 significant barrier when treating chronic obstructive pulmonary disease (COPD). 25 Erythromycin (EM) has been shown to have an anti-inflammatory role in some 26 chronic airway inflammatory diseases, particularly diffuse panbronchiolitis (DBP) 27 and cystic fibrosis. Here, we explored whether the combination therapy of EM and 28 dexamethasone (Dex) reverse corticosteroid insensitivity and investigated the 29 molecular mechanism by which this occurs. We demonstrated that the combination of 30 EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells 31 (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, 32 pre-treatment with 10 μg/ml, 50 μg/ml or 100 μg/ml EM reversed the HDAC2 protein 33 reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed 34 to CSE show a reduction in HDAC activity, which was potently reversed by EM or 35 combination treatment. While 10% and 17.5% CSE increased PAkt expression in a 36 concentration-dependent manner, pre-application of EM and the combination 37 treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by 38 CSE or EM treatments. Furthermore, the combination treatment enhanced 39 glucocorticoid receptor (GR)α expression. Our results demonstrate that the 40 combination therapy of EM and Dex can restore corticosteroid sensitivity through 41 inhibition of the PI3K-δ/Akt pathway and enhancing GRα expression. 42