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COX-1, and not COX-2 activity, regulates airway function: relevance to aspirin-sensitive asthma

Louise S. Harrington^*, Ruth Lucas^*, Shaun K. McMaster^*, Laura Moreno^*, Glenis Scadding^*, Timothy D. Warner and Jane A. Mitchell^*,1

^* Cardiothoracic Pharmacology, Cardiac Medicine, NHLI, Imperial College, London, UK; and

William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine and Dentistry, London, UK

¹ Correspondence: Cardiac Medicine, NHLI, Imperial College, Dovehouse St., London SW3 6LY, UK. E-mail: j.a.mitchell{at}ic.ac.uk

Cyclooxygenase (COX) -1 and COX-2 are expressed in airway cells, where their activities influence functions such as airway hyperreactivity. Clinical data show that mixed COX-1/COX-2 inhibitors such as aspirin, but not COX-2 selective inhibitors such as rofecoxib, induce bronchoconstriction and asthma in sensitive individuals. This anomaly has not yet been explained. Here, we have used tissue from genetically modified mice lacking functional COX-1 (COX-1^–/–), as well as airway tissue from "aspirin-sensitive" and control patients to address this issue. Bronchi from wild-type mice contained predominantly COX-1 immunoreactivity and contracted in vitro in response to acetylcholine and U46619. Bronchi from COX-1^–/– mice were hyperresponsive to bronchoconstrictors. Inhibitors of COX (naproxen, diclofenac, or ibuprofen) increased bronchoconstriction in tissue from wild-type but not from COX-1^–/– mice. Cells cultured from aspirin-sensitive or control human donors contained similar levels of COX-1 and COX-2 immunoreactivity. COX activity in cells from aspirin-sensitive or tolerant patients was inhibited by aspirin, SC560, which blocks COX-1 selectively, but not by rofecoxib, which is a selective inhibitor of COX-2. These observations show that despite the presence of COX-2, COX-1 is functionally predominant in the airways and explains clinical observations relating to drug specificity in patients with aspirin-sensitive asthma.—Harrington, L. S., Lucas, R., McMaster, S. K., Moreno, L., Scadding, G., Warner, T. D., Mitchell, J. A. COX-1, and not COX-2 activity, regulates airway function: relevance to aspirin-sensitive asthma.

Key Words: nonsteroid drugs • bronchoconstriction • prostaglandins