title: Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma.
abstract: BACKGROUND
  Patients with severe asthma are less responsive to corticosteroid therapy and show increased airway remodeling. The mesenchymal progenitors, fibrocytes, may be involved in the remodeling of asthmatic airways. We propose that fibrocytes in severe asthma are different from those in nonsevere asthma.
  
  
  OBJECTIVE
  To examine the survival, myofibroblastic differentiation, and C-C chemokine receptor 7 (CCR7) expression in blood fibrocytes from patients with severe and nonsevere asthma and study the effect of corticosteroids on fibrocyte function.
  
  
  METHODS
  The nonadherent non-T-cell fraction of blood mononuclear cells was isolated from healthy subjects and patients with nonsevere and severe asthma. Total and differentiating fibrocytes were identified by their expression of CD45, collagen I, and α-smooth muscle actin using flow cytometry. The expression of CCR7 and of the glucocorticoid receptor was measured by using flow cytometry.
  
  
  RESULTS
  Increased numbers of circulating fibrocytes, with greater myofibroblastic differentiation potential, were observed in patients with severe asthma. Dexamethasone induced apoptosis, leading to reduction in the number of cultured fibrocytes and total nonadherent non-T cells from healthy subjects and patients with nonsevere asthma but not from patients with severe asthma. Dexamethasone reduced CCR7 expression in fibrocytes from patients with nonsevere asthma but not from patients with severe asthma. Glucocorticoid receptor expression was attenuated in fibrocytes from patients with severe asthma.
  
  
  CONCLUSIONS
  Patients with severe asthma have elevated numbers of circulating fibrocytes that show enhanced myofibroblastic differentiation and that are less responsive to the effects of corticosteroids.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; NIHR Respiratory Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom; Department of Thoracic Medicine, Chang Gung Medical Foundation, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Lo
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; NIHR Respiratory Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Michaeloudes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; NIHR Respiratory Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Bhavsar
authors.affiliation: Department of Thoracic Medicine, Chang Gung Medical Foundation, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Chien-Da
authors.initials: CD
authors.lastname: Huang
authors.affiliation: Department of Thoracic Medicine, Chang Gung Medical Foundation, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Thoracic Medicine, Chang Gung Medical Foundation, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Han-Pin
authors.initials: HP
authors.lastname: Kuo
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; NIHR Respiratory Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom. Electronic address: f.chung@imperial.ac.uk.
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000175:diagnosis* / Q000188:drug therapy*; D016022:Case-Control Studies; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D003239:Connective Tissue Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D054400:Receptors, CCR7 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D054400:Receptors, CCR7; D011965:Receptors, Glucocorticoid
keywords: CCR7; Fibrocytes; PBMCs; asthma; corticosteroids; glucocorticoid receptor; myofibroblasts; nonadherent non-T cells; remodeling