title: Restoration of Corticosteroid Sensitivity in Chronic Obstructive Pulmonary Disease by Inhibition of Mammalian Target of Rapamycin.
abstract: BACKGROUND
  Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Several molecular mechanisms have been proposed, such as activations of the phosphoinositide-3-kinase/Akt pathway and p38 mitogen-activated protein kinase. However, the mechanism for corticosteroid resistance is still not fully elucidated.
  
  
  OBJECTIVE
  To investigate the role of mammalian target of rapamycin (mTOR) in corticosteroid sensitivity in COPD.
  
  
  METHODS
  The corticosteroid sensitivity of peripheral blood mononuclear cells collected from patients with COPD, smokers, and nonsmoking control subjects, or of human monocytic U937 cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-α-induced CXCL8 production in the presence or absence of the mTOR inhibitor rapamycin. mTOR activity was determined as the phosphorylation of p70 S6 kinase, using Western blotting.
  
  
  RESULTS
  mTOR activity was increased in peripheral blood mononuclear cells from patients with COPD, and treatment with rapamycin inhibited this as well as restoring corticosteroid sensitivity. In U937 cells, CSE stimulated mTOR activity and c-Jun expression, but pretreatment with rapamycin inhibited both and also reversed CSE-induced corticosteroid insensitivity.
  
  
  CONCLUSIONS
  mTOR inhibition by rapamycin restores corticosteroid sensitivity via inhibition of c-Jun expression, and thus mTOR is a potential novel therapeutic target for COPD.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Mitani
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Vuppusetty
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mercado
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D000368:Aged; D004351:Drug Resistance / Q000187:drug effects* / Q000276:immunology; D005260:Female; D056464:Histone Deacetylase 2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects* / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D020123:Sirolimus / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D012907:Smoking / Q000009:adverse effects / Q000503:physiopathology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects* / Q000502:physiology; D020298:U937 Cells / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology
chemical_list: D000305:Adrenal Cortex Hormones; D056464:Histone Deacetylase 2; D007166:Immunosuppressive Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C546842:MTOR protein, human
keywords: c-Jun; chronic obstructive pulmonary disease; corticosteroid resistance; mammalian target of rapamycin; rapamycin