title: Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients.
abstract: BACKGROUND
  Overexpression of the transcriptional regulatory factor activator protein 1 might contribute to T-cell glucocorticoid (GC) refractoriness in GC-resistant asthma.
  
  
  OBJECTIVE
  We sought to address the hypothesis that clinically GC-resistant asthma is accompanied by failure of systemic GCs to inhibit phosphorylation of c-jun and c-jun N-terminal kinase (JNK) in bronchial mucosal cells.
  
  
  METHODS
  We performed enumeration of total (CD45+) leukocytes and cells expressing c-fos and total and phosphorylated c-jun and JNK in bronchial biopsy sections from 9 GC-sensitive and 17 GC-resistant asthmatic patients taken before and after oral prednisolone (40 mg/1.72 m(2) body surface area daily for 14 days) using specific antibodies, immunohistochemistry, and image analysis.
  
  
  RESULTS
  At baseline, mean total (CD45+) mucosal leukocytes, total cells expressing phosphorylated c-jun and JNK, and mean percentages of cells in which these molecules were phosphorylated were similar in both groups, whereas mean total numbers of c-fos-immunoreactive cells were increased in the GC-resistant asthmatic subjects (P = .04). After prednisolone, the mean total cells expressing phosphorylated c-jun and JNK and the mean percentages of cells in which these molecules were phosphorylated were significantly reduced in the GC-sensitive (P < or = .02) but not the GC-resistant asthmatic subjects. Mean total CD45+ leukocytes and c-fos-immunoreactive cells were not significantly altered in either group.
  
  
  CONCLUSIONS
  Clinical GC responsiveness in asthma is accompanied by reduced phosphorylation of bronchial mucosal c-jun and JNK, a phenomenon not seen in resistant patients.
  
  
  CONCLUSIONS
  Dysregulation of activator protein 1 activation leading to clinical GC resistance might reflect identifiable environmental influences and is a target for future therapy.
authors.affiliation: King's College London, MRC, London SE1 9RT.
authors.forename: Tuck-Kay
authors.initials: TK
authors.lastname: Loke
authors.forename: Kirsty H
authors.initials: KH
authors.lastname: Mallett
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ratoff
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Connor
authors.forename: Sun
authors.initials: S
authors.lastname: Ying
authors.forename: Qiu
authors.initials: Q
authors.lastname: Meng
authors.forename: Cecilia
authors.initials: C
authors.lastname: Soh
authors.forename: Tak H
authors.initials: TH
authors.lastname: Lee
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Corrigan
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011239:Prednisolone / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D011239:Prednisolone; D048031:JNK Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens