Aspirin attenuates the anti-inflammatory effects of theophylline via inhibition of cAMP production in mice with non-eosinophilic asthma.
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.
Moon
Hyung-Geun
HG
Department of Life Science, POSTECH Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang, Korea.
Kim
You-Sun
YS
Choi
Jun-Pyo
JP
Choi
Dong-Sic
DS
Yoon
Chang Min
CM
Jeon
Seong Gyu
SG
Gho
Yong Song
YS
Kim
Yoon-Keun
YK
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D000242:Cyclic AMP / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011657:Pulmonary Eosinophilia / Q000188:drug therapy* / Q000378:metabolism; D013806:Theophylline / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D013806:Theophylline; D000242:Cyclic AMP; D001241:Aspirin