title: Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1.
abstract: BACKGROUND
  Asthma is associated with increased expression of a typical array of genes involved in immune and inflammatory responses, including those encoding the prototypic Th2 cytokines interleukin (IL) 4, IL-5, and IL-13. Most of these genes contain binding sites for activator protein-1 (AP-1) within their promoter and are therefore believed to depend on AP-1 for their expression, suggesting that this transcription factor could be of particular importance in asthma pathophysiology.
  
  
  OBJECTIVE
  To clarify the role of AP-1 in the effector phase of pulmonary allergy.
  
  
  METHODS
  Ovalbumin (OVA)-sensitized mice were intratracheally given decoy oligodeoxyribonucleotides (ODNs) specifically directed to AP-1 or scrambled control ODNs before challenge with aerosolized OVA. Twenty-four hours after the last OVA challenge, airway hyperresponsiveness was measured and allergic airway inflammation was evaluated quantitatively. AP-1 decoys were localized using flow cytometry and immunohistochemistry. AP-1 activity in the lung was assessed using electrophoretic mobility shift assay.
  
  
  RESULTS
  Intratracheally delivered AP-1 decoys efficiently targeted airway immune cells, thus precluding AP-1 activation on OVA challenge. Decoy-mediated local inhibition of AP-1 resulted in significant attenuation of all the pathophysiologic features of experimental asthma-namely, eosinophilic airway inflammation, airway hyperresponsiveness, mucous cell hyperplasia, production of allergen-specific immunoglobulins, and synthesis of IL-4, IL-5, and IL-13. Scrambled control ODNs had no detectable effects.
  
  
  CONCLUSIONS
  Our results reveal a key role for AP-1 in the effector phase of pulmonary allergy and indicate that specific AP-1 inhibition in the airways may have therapeutic value in the control of established asthma.
authors.affiliation: Laboratoire de Physiologie, Faculté de Médecine Vétérinaire, Centre de Thérapie Cellulaire et Moléculaire, Université de Liège, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Desmet
authors.forename: Philippe
authors.initials: P
authors.lastname: Gosset
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Henry
authors.forename: Virginie
authors.initials: V
authors.lastname: Garzé
authors.forename: Pedro
authors.initials: P
authors.lastname: Faisca
authors.forename: Nanda
authors.initials: N
authors.lastname: Vos
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jaspar
authors.forename: Dorothée
authors.initials: D
authors.lastname: Mélotte
authors.forename: Bart
authors.initials: B
authors.lastname: Lambrecht
authors.forename: Daniel
authors.initials: D
authors.lastname: Desmecht
authors.forename: Bernard
authors.initials: B
authors.lastname: Pajak
authors.forename: Muriel
authors.initials: M
authors.lastname: Moser
authors.forename: Pierre
authors.initials: P
authors.lastname: Lekeux
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bureau
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects; D005260:Female; D006967:Hypersensitivity / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D007107:Immune System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D014132:Trachea / Q000276:immunology / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D009838:Oligodeoxyribonucleotides; D018808:Transcription Factor AP-1; D010047:Ovalbumin