Exp Mol Med.  2010 Jan;42(1):47-60. 10.3858/emm.2010.42.1.005.

Aspirin attenuates the anti-inflammatory effects of theophylline via inhibition of cAMP production in mice with non-eosinophilic asthma

• Moon HG
• Kim YS
• Choi JP
• Choi DS
• Yoon CM
• Jeon SG
• Gho YS
• Kim YK

• KMID: 946669
• DOI: http://doi.org/10.3858/emm.2010.42.1.005

Abstract

Theophylline is commonly used to treat severe asthma and chronic obstructive pulmonary disease (COPD) characterized by non-eosinophilic inflammation. Acetyl salicylic acid (ASA) is one of the most widely used medications worldwide, but up to 20% of patients with asthma experience aggravated respiratory symptoms after taking ASA. Here we evaluated the adverse effect of ASA on the therapeutic effect of theophylline in mice with non-eosinophilic asthma. A non-eosinophilic asthma mouse model was induced by airway sensitization with lipopolysaccharide-containing allergen and then challenged with allergen alone. Therapeutic intervention was performed during allergen challenge. Theophylline inhibited lung inflammation partly induced by Th1 immune response. ASA attenuated the beneficial effects of theophylline. However, co-administration of the ASA metabolite salicylic acid (SA) showed no attenuating effect on theophylline treatment. The therapeutic effect of theophylline was associated with increase in cAMP levels, which was blocked by co-treatment of theophylline and ASA. ASA co-treatment also attenuated the anti-inflammatory effects of a specific phosphodiesterase 4 inhibitor. These results demonstrate that ASA reverses anti-inflammatory effects of theophylline, and that ASA exerts its adverse effects through the inhibition of cAMP production. Our data suggest that ASA reverses lung inflammation in patients taking theophylline, although clinical evidence will be needed.

Keyword

adverse effect; aspirin; asthma, aspirin-induced; cyclic AMP; cyclic nucleotide phosphodiesterases, type 4; drug toxicity; pneumonia; theophylline

MeSH Terms

Animals
Anti-Inflammatory Agents/*therapeutic use
Aspirin/*therapeutic use
Asthma/*drug therapy/*metabolism
Blotting, Western
Bronchoalveolar Lavage Fluid
Cyclic AMP/*metabolism
Enzyme-Linked Immunosorbent Assay
Immunoprecipitation
Mice
Mice, Inbred C57BL
Mice, Knockout
Pulmonary Eosinophilia/*drug therapy/metabolism
Theophylline/*therapeutic use