An intranasal selective antisense oligonucleotide impairs lung cyclooxygenase-2 production and improves inflammation, but worsens airway function, in house dust mite sensitive mice.
BACKGROUND
Despite its reported pro-inflammatory activity, cyclooxygenase (COX)-2 has been proposed to play a protective role in asthma. Accordingly, COX-2 might be down-regulated in the airway cells of asthmatics. This, together with results of experiments to assess the impact of COX-2 blockade in ovalbumin (OVA)-sensitized mice in vivo, led us to propose a novel experimental approach using house dust mite (HDM)-sensitized mice in which we mimicked altered regulation of COX-2.


METHODS
Allergic inflammation was induced in BALBc mice by intranasal exposure to HDM for 10 consecutive days. This model reproduces spontaneous exposure to aeroallergens by asthmatic patients. In order to impair, but not fully block, COX-2 production in the airways, some of the animals received an intranasal antisense oligonucleotide. Lung COX-2 expression and activity were measured along with bronchovascular inflammation, airway reactivity, and prostaglandin production.


RESULTS
We observed impaired COX-2 mRNA and protein expression in the lung tissue of selective oligonucleotide-treated sensitized mice. This was accompanied by diminished production of mPGE synthase and PGE2 in the airways. In sensitized mice, the oligonucleotide induced increased airway hyperreactivity (AHR) to methacholine, but a substantially reduced bronchovascular inflammation. Finally, mRNA levels of hPGD synthase remained unchanged.


CONCLUSIONS
Intranasal antisense therapy against COX-2 in vivo mimicked the reported impairment of COX-2 regulation in the airway cells of asthmatic patients. This strategy revealed an unexpected novel dual effect: inflammation was improved but AHR worsened. This approach will provide insights into the differential regulation of inflammation and lung function in asthma, and will help identify pharmacological targets within the COX-2/PG system.
Torres
Rosa
R
Department of Pneumology and Respiratory Allergy, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain. rosa.torres@uab.cat
Herrerias
Aida
A
Serra-Pagès
Mariona
M
Roca-Ferrer
Jordi
J
Pujols
Laura
L
Marco
Alberto
A
Picado
César
C
de Mora
Fernando
F
D000281:Administration, Intranasal; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000503:physiopathology* / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D004391:Dust; D005260:Female; D008168:Lung / Q000187:drug effects / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics*; D039981:Pyroglyphidae
D004391:Dust; D016376:Oligonucleotides, Antisense; D051546:Cyclooxygenase 2