title: Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages.
abstract: BACKGROUND
  The cause of corticosteroid-resistant (CR) asthma is unknown.
  
  
  OBJECTIVE
  We sought to perform gene microarray analyses by using bronchoalveolar lavage (BAL) cells from well-characterized subjects with CR asthma and subject with corticosteroid-sensitive (CS) asthma to elucidate the differential expression of genes that contribute to the development of corticosteroid resistance.
  
  
  METHODS
  The patients were characterized as having CR or CS asthma based on FEV(1) percent predicted improvement after a 1-week course of oral prednisone. Expression of selected gene targets was verified by means of real-time PCR and ELISA.
  
  
  RESULTS
  Microarray analyses demonstrated significantly higher levels (>3-fold increase, P < .05) of transcripts for TNF-alpha, IL-1 alpha, IL-1 beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, and CCL20 in BAL cells of subjects with CR asthma. These findings, confirmed by means of RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively activated macrophages, arginase I and CCL24, were decreased. Genes associated with activation of the LPS signaling pathway (early growth response 1, dual-specificity phosphatase 2, molecule possessing ankyrin repeats induced by LPS, and TNF-alpha-induced protein 3) were significantly increased in BAL samples from subjects with CR asthma (P < .05). These patients had significantly higher amounts (1444.0 +/- 457.3 pg/mg total protein) of LPS in BAL fluid than seen in subjects with CS asthma (270.5 +/- 216.0 pg, P < .05), as detected by using the LAL assay and confirmed by means of gas chromatographic/mass spectrometric analysis. Prolonged exposure to LPS induced functional steroid resistance to dexamethasone in normal human monocytes, as demonstrated by persistently increased IL-6 levels in the presence of dexamethasone.
  
  
  CONCLUSIONS
  Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from subjects with CR asthma suggest that LPS exposure might contribute to CR asthma.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Goleva
authors.forename: Pia J
authors.initials: PJ
authors.lastname: Hauk
authors.forename: Clifton F
authors.initials: CF
authors.lastname: Hall
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Liu
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000032:analysis / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011241:Prednisone / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D015850:Interleukin-6; D008070:Lipopolysaccharides; D003907:Dexamethasone; D011241:Prednisone
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