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J Allergy Clin Immunol. 2012 Oct;130(4):877-85.e5. doi: 10.1016/j.jaci.2012.07.017. Epub 2012 Sep 1.

Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma.

Author information

1
Airway Disease, National Heart and Lung Institute, Imperial College London, and the Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom.

Abstract

BACKGROUND:

Patients with severe asthma are less responsive to the beneficial effects of corticosteroid therapy.

OBJECTIVE:

We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.

METHODS:

ASMCs 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.

RESULTS:

CCL11 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.

CONCLUSIONS:

ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.

PMID:
22947346
PMCID:
PMC3578224
DOI:
10.1016/j.jaci.2012.07.017
[Indexed for MEDLINE]
Free PMC Article

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