ASTHMA

Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma

P Bhavsar, M Hew, N Khorasani, A Torrego, P J Barnes, I Adcock, K F Chung

Section of Airways Disease, National Heart & Lung Institute, Imperial College & Royal Brompton and Harefield NHS Trust Hospital, London, UK

Professor K F Chung, National Heart & Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK; f.chung{at}imperial.ac.uk

Background: About 5–10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1).

Methods: Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 µg/ml) and dexamethasone (10^–8 and 10^–6 M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts.

Results: The inhibition of LPS-induced interleukin (IL)1β, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1 release by dexamethasone (10^–6 M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma.

Conclusion: Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Barnes, P. J. (2009). Histone deacetylase-2 and airway disease. Ther Adv Respir Dis 3: 235-243 [Abstract]  
• Kane, B., Kolsum, U., Southworth, T., Armstrong, J., Woodcock, A., Singh, D. (2009). The Effects of Smoking on the Lipopolysaccharide Response and Glucocorticoid Sensitivity of Alveolar Macrophages of Patients With Asthma. Chest 136: 163-170 [Abstract] [Full Text]  
• Gaga, M., Zervas, E., Chanez, P. (2009). Update on severe asthma: what we know and what we need. ERR 18: 58-65 [Full Text]  
• Clark, A. R., Martins, J. R. S., Tchen, C. R. (2008). Role of Dual Specificity Phosphatases in Biological Responses to Glucocorticoids. J. Biol. Chem. 283: 25765-25769 [Abstract] [Full Text]