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


CONCLUSIONS
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.
Bhavsar
P
P
National Heart & Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK.
Hew
M
M
Khorasani
N
N
Torrego
A
A
Barnes
P J
PJ
Adcock
I
I
Chung
K F
KF
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001999:Bronchoscopy; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D005260:Female; D005336:Fiber Optic Technology; D005541:Forced Expiratory Volume / Q000502:physiology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D011239:Prednisolone / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014797:Vital Capacity / Q000502:physiology
D000305:Adrenal Cortex Hormones; D016207:Cytokines; D008070:Lipopolysaccharides; D003907:Dexamethasone; D011239:Prednisolone; D054638:Dual Specificity Phosphatase 1