title: The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD.
abstract: BACKGROUND
  Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however.
  
  
  METHODS
  Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays.
  
  
  RESULTS
  MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR.
  
  
  CONCLUSIONS
  MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, NIHR Respiratory Biomedical Research Unit at the Royal Brompton NHS Foundation Trust and Imperial College London, London, United Kingdom.
authors.forename: Kirsty E
authors.initials: KE
authors.lastname: Russell
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, NIHR Respiratory Biomedical Research Unit at the Royal Brompton NHS Foundation Trust and Imperial College London, London, United Kingdom.
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, NIHR Respiratory Biomedical Research Unit at the Royal Brompton NHS Foundation Trust and Imperial College London, London, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Clarke
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, NIHR Respiratory Biomedical Research Unit at the Royal Brompton NHS Foundation Trust and Imperial College London, London, United Kingdom.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Durham
authors.affiliation: Airway Disease Infection Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mallia
authors.affiliation: Airway Disease Infection Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Joseph
authors.initials: J
authors.lastname: Footitt
authors.affiliation: Airway Disease Infection Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, NIHR Respiratory Biomedical Research Unit at the Royal Brompton NHS Foundation Trust and Imperial College London, London, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: RRI DPU, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Hall
authors.affiliation: RRI DPU, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Simpson
authors.affiliation: Priority Research Centre for Respiratory Diseases, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Starkey
authors.affiliation: Priority Research Centre for Respiratory Diseases, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, NIHR Respiratory Biomedical Research Unit at the Royal Brompton NHS Foundation Trust and Imperial College London, London, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, NIHR Respiratory Biomedical Research Unit at the Royal Brompton NHS Foundation Trust and Imperial College London, London, United Kingdom.
authors.forename: Coen H
authors.initials: CH
authors.lastname: Wiegman
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007555:Isoxazoles / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010126:Ozone; D011014:Pneumonia / Q000150:complications* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects; D013183:Sputum / Q000187:drug effects / Q000378:metabolism
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000305:Adrenal Cortex Hormones; D016207:Cytokines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D010126:Ozone; D003907:Dexamethasone