Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 130, Issue 4, Pages 877-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2012.07.017
Keywords
Airway smooth muscle; asthma; corticosteroid insensitivity; CX3CL1; CCL11; CXCL8
Categories
Funding
- Wellcome Trust [085935]
- Asthma UK [08/041]
- Respiratory Disease Biomedical Research Unit at the Royal Brompton NHS Foundation Trust
- Imperial College London
- GlaxoSmithKline
- Medical Research Council UK
- Asthma UK
- Wellcome Trust
- Asthma UK [08/041] Funding Source: researchfish
- Medical Research Council [G0801056B] Funding Source: researchfish
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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-alpha- and IFN-gamma-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-alpha. Dexamethasone potentiated TNF-alpha- and IFN-gamma-induced CX3CL1 release equally in all 3 groups. TNF-alpha-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-alpha-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. Ap38 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. (J Allergy Clin Immunol 2012; 130:877-85.)
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