Published ahead of print on June 16, 2005, doi:10.1164/rccm.200410-1431OC Am. J. Respir. Crit. Care Med., Volume 172, Number 6, September 2005, 671-678 A more recent version of this article appeared on September 15, 2005
Submitted on October 29, 2004 Treatment of Experimental Asthma by Decoy-mediated Local Inhibition of Activator Protein-1Christophe Desmet1,1 Laboratoire de Physiologie, Faculte de Medecine Veterinaire, Centre de Therapie Cellulaire et Moleculaire, Universite de Liege, Liege, Belgium, 2 Institut National de la Sante et de la Recherche Medicale, Unite 416, Institut Pasteur de Lille, Lille Cedex, France, 3 Laboratoire de Physiologie Animale, Institut de Biologie et de Medecine Moleculaires, Universite Libre de Bruxelles, Gosselies, Belgium, 4 Laboratoire de Pathologie, Faculte de Medecine Veterinaire, Universite de Liege, Liege, Belgium, 5 Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands, 6 Laboratoire de Physiologie, Faculte de Medecine Veterinaire, Centre de Therapie Cellulaire et Moleculaire, Universite de Liege, Liege, Belgium; Laboratoire de Physiologie Animale, Institut de Biologie et de Medecine Moleculaires, Universite Libre de Bruxelles, Gosselies, Belgium * To whom correspondence should be addressed. 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 prototypical Th2 cytokines interleukin (IL)-4, IL-5 and IL-13. Most of these genes contain binding sites for activator protein (AP)-1 within their promoter and are therefore thought 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. 24 hours after the last OVA challenge, airway hyperresponsiveness (AHR) 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 upon OVA challenge. Decoy-mediated local inhibition of AP-1 resulted in significant attenuation of all the pathophysiological features of experimental asthma, namely eosinophilic airway inflammation, AHR, mucous cells 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
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