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)-1α 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.
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PB and MH contributed equally to the work.
Funding: This work was supported by NIH RO-1 grant HL-69155 and was conducted within the Severe Asthma Research Program (SARP) whose principal investigators were E Israel, Brigham and Women’s Hospital; SC Erzurum, Cleveland Clinic; WG Teague, Emory University; KF Chung, Imperial College London; SE Wenzel, National Jewish Medical and Research Center; WJ Calhoun, University of Texas; B Gaston, University of Virginia; WW Busse, University of Wisconsin; ER Bleecker, Wake Forest University; M Castro, Washington University in St Louis.
Competing interests: None.
Ethics approval: The study protocol was approved by the National Heart and Lung Institute and Royal Brompton Hospital Ethics Committee. All volunteers gave written informed consent to participate in the study.
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