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Published on: July 10, 2018
Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice
Wei Duan1, Jasmine H P Chan, Kelly McKay
1Department of Pharmacology, Faculty of Medicine, National University of Singapore, MD2, 18 Medical Drive, Singapore 117597.
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 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.
Insights
Inhaled p38alpha MAPK antisense oligonucleotide (ASO) reduced airway inflammation and hyperresponsiveness in a mouse asthma model. This study demonstrates the potential of inhaled ASO therapy for inflammatory lung diseases like asthma.
Area of Science:
- Molecular Biology
- Immunology
- Pharmacology
Background:
- p38 mitogen-activated protein kinase (MAPK) is crucial for inflammatory cell activation.
- Asthma involves inflammatory cell activation and airway hyperresponsiveness.
- Targeting p38alpha MAPK may offer a therapeutic strategy for asthma.
Purpose of the Study:
- To investigate the anti-inflammatory effects of inhaled p38alpha MAPK antisense oligonucleotide (p38alpha-ASO) in a mouse model of asthma.
- To assess the efficacy of aerosolized p38alpha-ASO in reducing airway inflammation and hyperresponsiveness.
Main Methods:
- Characterization of a potent and selective p38alpha-ASO in vitro.
- Inhalation of aerosolized p38alpha-ASO in an ovalbumin (OVA)-induced mouse asthma model.
- Measurement of inflammatory cells, cytokines (IL-4, IL-5, IL-13), mucus, and airway hyperresponsiveness in bronchoalveolar lavage fluid and lung tissue.
- Quantitative PCR to assess p38alpha MAPK mRNA expression.
Main Results:
- Inhaled p38alpha-ASO significantly reduced OVA-induced increases in total cells, eosinophils, IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid.
- Dose-dependent inhibition of airway hyperresponsiveness and reduction in lung tissue eosinophilia and mucus hypersecretion were observed.
- p38alpha-ASO significantly reduced p38alpha MAPK mRNA expression in lung cells.
- Effects were specific to p38alpha-ASO, as a control oligonucleotide showed no significant impact.
Conclusions:
- Aerosol delivery of p38alpha-ASO demonstrates pharmacodynamic activity in the airways.
- Inhaled p38alpha-ASO effectively reduces airway inflammation and hyperresponsiveness in a mouse asthma model.
- p38alpha MAPK ASO holds therapeutic potential for asthma and other inflammatory lung diseases.
