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

Am J Respir Crit Care Med. 2005 Mar 15;171(6):571-8. doi: 10.1164/rccm.200408-1006OC. Epub 2004 Nov 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Aerosols
  • Animals
  • Asthma / physiopathology
  • Asthma / 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


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