title: Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma.
abstract: BACKGROUND
  Patients with severe asthma are less responsive to the beneficial effects of corticosteroid therapy.
  
  
  OBJECTIVE
  We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.
  
  
  METHODS
  ASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n = 12) and patients with nonsevere (n = 10) or severe (n = 10) asthma were compared for the effect of dexamethasone on suppression of TNF-α- and IFN-γ-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined.
  
  
  RESULTS
  CCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-α. Dexamethasone potentiated TNF-α- and IFN-γ-induced CX3CL1 release equally in all 3 groups. TNF-α-induced phosphorylated p38 mitogen-activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-α-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A p38 inhibitor increased the inhibitory effect of dexamethasone.
  
  
  CONCLUSIONS
  ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.
authors.affiliation: Airway Disease, National Heart and Lung Institute, Imperial College London, and the Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom.
authors.forename: Po-Jui
authors.initials: PJ
authors.lastname: Chang
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Bhavsar
authors.forename: Charalambos
authors.initials: C
authors.lastname: Michaeloudes
authors.forename: Nadia
authors.initials: N
authors.lastname: Khorasani
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051996:Transcription Factor RelA / Q000502:physiology
chemical_list: D018925:Chemokines; D051996:Transcription Factor RelA; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases