Published ahead of print on June 16, 2005, doi:10.1164/rccm.200410-1431OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200410-1431OC Treatment of Experimental Asthma by Decoy-mediated Local Inhibition of Activator Protein-1Laboratoires de Physiologie and de Pathologie, Faculté de Médecine Vétérinaire, Centre de Thérapie Cellulaire et Moléculaire, Université de Liège, Liège; Laboratoire de Physiologie Animale, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium; Institut National de la Santé et de la Recherche Médicale, Institut Pasteur de Lille, Lille, France; and Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands Correspondence and requests for reprints should be addressed to Fabrice Bureau, D.V.M., Ph.D., Laboratoire de Physiologie, Faculté de Médecine Vétérinaire, Centre de Thérapie Cellulaire et Moléculaire, Université de Liège, Boulevard de Colonster, Bâtiment B42, Sart-Tilman, B-4000 Liège, Belgium. E-mail: fabrice.bureau{at}ulg.ac.be Rationale: 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. Measurements and Main 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.
Key Words: allergy • eosinophils • gene therapy • lung • transcription factors This article has been cited by other articles:
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