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Inhaled p38a mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice
journal contribution
posted on 2005-03-15, 00:00 authored by Wei DuanWei Duan, J H P Chan, K McKay, J R Crosby, H H Choo, B P Leung, J G Karras, W S F WongThe 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 p38alpha MAPK antisense oligonucleotide (p38alpha-ASO) in a mouse asthma model. A potent and selective p38alpha-ASO was characterized in vitro. Inhalation of aerosolized p38alpha-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 p38alpha-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 p38alpha-ASO significantly reduced p38alpha MAPK mRNA expression. Nose-only aerosol exposure of mice verified the p38alpha-ASO-induced inhibition of OVA-induced pulmonary eosinophilia, mucus hypersecretion, and airway hyperresponsiveness. None of the effects of the p38alpha-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 p38alpha MAPK ASO approach may have therapeutic potential for asthma and other inflammatory lung diseases.
History
Journal
American journal of respiratory and critical care medicineVolume
171Issue
6Pagination
571 - 578Publisher
American Thoracic SocietyLocation
New York, N.Y.Publisher DOI
ISSN
1073-449XLanguage
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
[2005, ATS]Usage metrics
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