Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice.
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.
Duan
Wei
W
Department of Pharmacology, Faculty of Medicine, National University of Singapore, MD2, 18 Medical Drive, Singapore 117597.
Chan
Jasmine H P
JH
McKay
Kelly
K
Crosby
Jeffrey R
JR
Choo
Hui Hwa
HH
Leung
Bernard P
BP
Karras
James G
JG
Wong
W S Fred
WS
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001249:Asthma / Q000503:physiopathology / Q000517:prevention & control*; D016535:Bronchial Hyperreactivity; D001992:Bronchoalveolar Lavage Fluid; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D048308:Mitogen-Activated Protein Kinase 14 / Q000008:administration & dosage*; D009093:Mucus / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D010047:Ovalbumin / Q000276:immunology; D016133:Polymerase Chain Reaction; D011657:Pulmonary Eosinophilia / Q000517:prevention & control
D000336:Aerosols; D016376:Oligonucleotides, Antisense; D010047:Ovalbumin; D048308:Mitogen-Activated Protein Kinase 14