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Published ahead of print on November 19, 2004, doi:10.1164/rccm.200408-1006OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 571-578, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200408-1006OC

Original Article

Inhaled p38{alpha} Mitogen-activated Protein Kinase Antisense Oligonucleotide Attenuates Asthma in Mice

Wei Duan, Jasmine H. P. Chan, Kelly McKay, Jeffrey R. Crosby, Hui Hwa Choo, Bernard P. Leung, James G. Karras and W. S. Fred Wong

Department of Pharmacology, National University of Singapore; Department of Rheumatology, Allergy, and Immunology, Tan Tock Seng Hospital, Singapore; Department of Antisense Drug Discovery, ISIS Pharmaceuticals, Carlsbad, California

Correspondence and requests for reprints should be addressed to W.S. Fred Wong, Ph.D., Department of Pharmacology, Faculty of Medicine, National University of Singapore, MD2, 18 Medical Drive, Singapore 117597. E-mail: phcwongf{at}nus.edu.sg

The p38 mitogen-activated protein kinase (MAPK) plays a critical role in the activation of inflammatory cells. Therefore, we investigated the antiinflammatory effects of a respirable p38{alpha} MAPK antisense oligonucleotide (p38{alpha}-ASO) in a mouse asthma model. A potent and selective p38{alpha}-ASO was characterized in vitro. Inhalation of aerosolized p38{alpha}-ASO using an aerosol chamber dosing system produced measurable lung deposition of ASO and significant reduction of ovalbumin (OVA-)-induced increases in total cells, eosinophils, and interleukin 4 (IL-4), IL-5, and IL-13 levels in bronchoalveolar lavage fluid, and dose-dependent inhibition of airway hyperresponsiveness in allergen-challenged mice. Furthermore, inhaled p38{alpha}-ASO markedly inhibited OVA-induced lung tissue eosinophilia and airway mucus hypersecretion. Quantitative polymerase chain reaction analysis of bronchoalveolar lavage fluid cells and peribronchial lymph node cells showed that p38{alpha}-ASO significantly reduced p38{alpha} MAPK mRNA expression. Nose-only aerosol exposure of mice verified the p38{alpha}-ASO–induced inhibition of OVA-induced pulmonary eosinophilia, mucus hypersecretion, and airway hyperresponsiveness. None of the effects of the p38{alpha}-ASO were produced by a six-base mismatched control oligonucleotide. These findings demonstrate antisense pharmacodynamic activity in the airways after aerosol delivery and suggest that a p38{alpha} MAPK ASO approach may have therapeutic potential for asthma and other inflammatory lung diseases.

Key Words: asthma • bronchoalveolar lavage fluid • eosinophilia • mucus hypersecretion • ovalbumin




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