title: A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial-mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study.
abstract: BACKGROUND
  We recently reported that epithelial-mesenchymal transition (EMT) is active in the airways in chronic obstructive pulmonary disease (COPD), suggesting presence of an active profibrotic and promalignant stroma. With no data available on potential treatment effects, we undertook a blinded analysis of inhaled corticosteroids (ICS) effects versus placebo on EMT markers in previously obtained endobronchial biopsies in COPD patients, as a "proof of concept" study.
  
  
  METHODS
  Assessment of the effects of inhaled fluticasone propionate (FP; 500 μg twice daily for 6 months) versus placebo in 34 COPD patients (23 on fluticasone propionate and eleven on placebo). The end points were epidermal growth factor receptor (EGFR; marker of epithelial activation) and the biomarkers of EMT: reticular basement membrane (Rbm) fragmentation ("hallmark" structural marker), matrix metalloproteinase-9 (MMP-9) cell expression, and S100A4 expression in basal epithelial and Rbm cells (mesenchymal transition markers).
  
  
  RESULTS
  Epithelial activation, "clefts/fragmentation" in the Rbm, and changes in the other biomarkers all regressed on ICS, at or close to conventional levels of statistical significance. From these data, we have been able to nominate primary and secondary end points and develop power calculations that would be applicable to a definitive prospective study.
  
  
  CONCLUSIONS
  Although only a pilot "proof of concept" study, this trial provided strong suggestive support for an anti-EMT effect of ICS in COPD airways. A larger and fully powered prospective study is now indicated as this issue is likely to be extremely important. Such studies may clarify the links between ICS use and better clinical outcomes and protection against lung cancer in COPD.
authors.affiliation: National Health and Medical Research Council Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Sukhwinder Singh
authors.initials: SS
authors.lastname: Sohal
authors.affiliation: National Health and Medical Research Council Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Amir
authors.initials: A
authors.lastname: Soltani
authors.affiliation: National Health and Medical Research Council Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia ; Iron Metabolism Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Reid
authors.affiliation: National Health and Medical Research Council Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia ; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Ward
authors.affiliation: National Health and Medical Research Council Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia ; Department of Biostatistics, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Wills
authors.affiliation: National Health and Medical Research Council Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: H Konrad
authors.initials: HK
authors.lastname: Muller
authors.affiliation: National Health and Medical Research Council Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Eugene Haydn
authors.initials: EH
authors.lastname: Walters
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D056151:Airway Remodeling / Q000187:drug effects*; D000730:Androstadienes / Q000008:administration & dosage*; D001315:Australia; D015415:Biomarkers / Q000378:metabolism; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000068298:Fluticasone; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D000730:Androstadienes; D015415:Biomarkers; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D000068298:Fluticasone; C512478:EGFR protein, human; D066246:ErbB Receptors; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: EGFR; MMP-9; S100A4; lung cancer; pilot trial; reticular basement membrane