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Published ahead of print on November 19, 2004, doi:10.1164/rccm.200408-1006OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 6, March 2005, 571-578

A more recent version of this article appeared on March 15, 2005
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Submitted on August 4, 2004
Accepted on November 16, 2004

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

Wei Duan1, Jasmine H.P. Chan1, Kelly McKay2, Jeffrey R Crosby2, Hui Hwa Choo1, Bernard P Leung3, James G Karras2, and W.S. Fred Wong1*

1 Department of Pharmacology, National University of Singapore, Singapore, 2 Department of Antisense Drug Discovery, ISIS Pharmaceuticals, Carlsbad, CA, USA, 3 Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore

* To whom correspondence should be addressed. 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 anti-inflammatory 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-induced increases in total cells, eosinophils, and IL-4, IL-5, and IL-13 levels in bronchoalveolar lavage fluid, as well as dose-dependent inhibition of airway hyperresponsiveness in allergen-challenged mice. Further, inhaled p38{alpha}-ASO markedly inhibited ovalbumin-induced lung tissue eosinophilia and airway mucus hypersecretion. Quantitative PCR analysis of bronchoalveolar lavage fluid cells and peri-bronchial 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 ovalbumin-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 following 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, ovalbumin, bronchoalveolar lavage fluid, mucus hypersecretion, eosinophilia




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