Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice.

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.

• Authors: Wei Duan, Jasmine H P Chan, Kelly McKay, Jeffrey R Crosby, Hui Hwa Choo, Bernard P Leung, James G Karras, W S Fred Wong
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 171 Issue 6 Pg. 571-8 (Mar 15 2005) ISSN: 1073-449X [Print] United States
• PMID: 15557129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aerosols
• Oligonucleotides, Antisense
• Ovalbumin
• Mitogen-Activated Protein Kinase 14

Topics

• Administration, Inhalation
• Aerosols
• Animals
• Asthma (physiopathology, prevention & control)
• Bronchial Hyperreactivity
• Bronchoalveolar Lavage Fluid
• Male
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinase 14 (administration & dosage)
• Mucus (metabolism)
• Oligonucleotides, Antisense (administration & dosage)
• Ovalbumin (immunology)
• Polymerase Chain Reaction
• Pulmonary Eosinophilia (prevention & control)