• Po-Jui Chang, Pankaj K Bhavsar, Charalambos Michaeloudes, Nadia Khorasani, and Kian Fan Chung.
• Airway Disease, National Heart and Lung Institute, Imperial College London, and the Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom.
• J. Allergy Clin. Immunol. 2012 Oct 1;130(4):877-85.e5.

BackgroundPatients with severe asthma are less responsive to the beneficial effects of corticosteroid therapy.ObjectiveWe investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.MethodsASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n = 12) and patients with nonsevere (n = 10) or severe (n = 10) asthma were compared for the effect of dexamethasone on suppression of TNF-α- and IFN-γ-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined.ResultsCCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-α. Dexamethasone potentiated TNF-α- and IFN-γ-induced CX3CL1 release equally in all 3 groups. TNF-α-induced phosphorylated p38 mitogen-activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-α-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A p38 inhibitor increased the inhibitory effect of dexamethasone.ConclusionsASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

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