Objectives: About 5-10% of patients with asthma suffer from poorly-controlled disease despite corticosteroid (CS) therapy, which may indicate the presence of CS insensitivity. We determined whether relative CS insensitivity is present in alveolar macrophages (AMs) from severe asthma patients and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1).
Methods: Fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 19 severe and 20 non-severe asthma patients, and for comparison, in 14 normal volunteers. AMs were exposed to lipopolysaccharide (LPS, 10 ug/ml) and dexamethasone (10-8 and 10-6M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA (mRNA) expression were assayed in cell extracts.
Results: The inhibition of LPS-induced IL-1b, IL-6, IL-8, MCP-1 and MIP-1b release by dexamethasone (10-6M) was significantly less in AMs from severe asthma compared to AMs from non-severe asthma. There was increased p38 MAPK activation in AMs from severe asthma patients. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma.
Conclusion: AMs from patients with severe asthma demonstrate corticosteroid insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.
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