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

Thorax. 2008 Sep;63(9):784-90. doi: 10.1136/thx.2007.090027. Epub 2008 May 20.

Abstract

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 mug/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)1beta, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use*
  • Adult
  • Asthma / drug therapy*
  • Asthma / enzymology
  • Asthma / pathology
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoscopy
  • Cytokines / metabolism*
  • Dexamethasone / pharmacology
  • Drug Resistance
  • Dual Specificity Phosphatase 1 / metabolism*
  • Female
  • Fiber Optic Technology
  • Forced Expiratory Volume / physiology
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages, Alveolar / drug effects*
  • Macrophages, Alveolar / enzymology
  • Male
  • Prednisolone / therapeutic use
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vital Capacity / physiology

Substances

  • Adrenal Cortex Hormones
  • Cytokines
  • Lipopolysaccharides
  • Dexamethasone
  • Prednisolone
  • Dual Specificity Phosphatase 1