Inhaled p38α Mitogen-activated Protein Kinase Antisense Oligonucleotide Attenuates Asthma in Mice

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Abstract
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 p38α MAPK antisense oligonucleotide (p38α-ASO) in a mouse asthma model. A potent and selective p38α-ASO was characterized in vitro. Inhalation of aerosolized p38α-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 p38α-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 p38α-ASO significantly reduced p38α MAPK mRNA expression. Nose-only aerosol exposure of mice verified the p38α-ASO–induced inhibition of OVA-induced pulmonary eosinophilia, mucus hypersecretion, and airway hyperresponsiveness. None of the effects of the p38α-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 p38α MAPK ASO approach may have therapeutic potential for asthma and other inflammatory lung diseases.

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