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RATIONALE: Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Several molecular mechanisms have been proposed, such as activations of the phosphoinositide-3-kinase/Akt pathway and p38 mitogen-activated protein kinase. However, the mechanism for corticosteroid resistance is still not fully elucidated. OBJECTIVES: To investigate the role of mammalian target of rapamycin (mTOR) in corticosteroid sensitivity in COPD. METHODS: The corticosteroid sensitivity of peripheral blood mononuclear cells collected from patients with COPD, smokers, and nonsmoking control subjects, or of human monocytic U937 cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-α-induced CXCL8 production in the presence or absence of the mTOR inhibitor rapamycin. mTOR activity was determined as the phosphorylation of p70 S6 kinase, using Western blotting. MEASUREMENTS AND MAIN RESULTS: mTOR activity was increased in peripheral blood mononuclear cells from patients with COPD, and treatment with rapamycin inhibited this as well as restoring corticosteroid sensitivity. In U937 cells, CSE stimulated mTOR activity and c-Jun expression, but pretreatment with rapamycin inhibited both and also reversed CSE-induced corticosteroid insensitivity. CONCLUSIONS: mTOR inhibition by rapamycin restores corticosteroid sensitivity via inhibition of c-Jun expression, and thus mTOR is a potential novel therapeutic target for COPD.

Original publication

DOI

10.1164/rccm.201503-0593OC

Type

Journal article

Journal

Am J Respir Crit Care Med

Publication Date

15/01/2016

Volume

193

Pages

143 - 153

Keywords

c-Jun, chronic obstructive pulmonary disease, corticosteroid resistance, mammalian target of rapamycin, rapamycin, Adrenal Cortex Hormones, Aged, Drug Resistance, Female, Histone Deacetylase 2, Humans, Immunosuppressive Agents, Male, Middle Aged, Oxidative Stress, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-jun, Pulmonary Disease, Chronic Obstructive, Sirolimus, Smoking, TOR Serine-Threonine Kinases, U937 Cells, p38 Mitogen-Activated Protein Kinases