title: Combination of erythromycin and dexamethasone improves corticosteroid sensitivity induced by CSE through inhibiting PI3K-δ/Akt pathway and increasing GR expression.
abstract: Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a significant barrier when treating chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been shown to have an anti-inflammatory role in some chronic airway inflammatory diseases, particularly diffuse panbronchiolitis and cystic fibrosis. Here, we explored whether the combination therapy of EM and dexamethasone (Dex) reverses corticosteroid insensitivity and investigated the molecular mechanism by which this occurs. We demonstrated that the combination of EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, pretreatment with 10, 50, or 100 μg/ml EM reversed the HDAC2 protein reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed to CSE show a reduction in histone deacetylase (HDAC) activity, which was potently reversed by EM or combination treatment. Although 10 and 17.5% CSE increased phosphorylated Akt (PAkt) expression in a concentration-dependent manner, preapplication of EM and the combination treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by CSE or EM treatments. Furthermore, the combination treatment enhanced glucocorticoid receptor (GR)α expression. Our results demonstrate that the combination therapy of EM and Dex can restore corticosteroid sensitivity through inhibition of the PI3K-δ/Akt pathway and enhancing GRα expression.
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Xue-Jiao
authors.identifier: http://orcid.org/0000-0003-1084-586X
authors.initials: XJ
authors.lastname: Sun
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Zhan-Hua
authors.initials: ZH
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Guang
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Jing-Min
authors.initials: JM
authors.lastname: Deng
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Guang-Nan
authors.initials: GN
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Li
authors.affiliation: EIGI Colt Laboratory, Medical Research Council Center for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: MacNee
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and xnzhong101@sina.com.
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Zhong
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; and.
authors.forename: Zhi-Yi
authors.initials: ZY
authors.lastname: He
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D016022:Case-Control Studies; D003907:Dexamethasone / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D004917:Erythromycin / Q000494:pharmacology*; D005765:Gastrointestinal Agents / Q000494:pharmacology; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*; D020298:U937 Cells
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D016209:Interleukin-8; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D004917:Erythromycin; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D056464:Histone Deacetylase 2
keywords: chronic obstructive pulmonary disease; corticosteroid insensitivity; erythromycin; glucocorticoid receptor; histone deacetylase 2