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

Abstract

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.

Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice

“…31 In patients with AIA, PGE 2 generation in response to proinflammatory stimuli by fibroblasts from both bronchioles 32 and nasal mucosal tissue 17,33 was markedly suppressed. In rodents with allergic airway inflammation, blockage of PGE 2 production by genetic deletion of the COX-1 enzyme 17,18 or pharmacologic inhibition by NSAIDs led to an increase in AHR, which depends on T H 2 cytokines. Interestingly, decreased EP2 receptor expression was reported in immune cells from patients with AIA, 34 and polymorphisms in EP2 and other EP receptor genes are associated with AIA.…”

Urinary excretion of lipid mediators in response to repeated eucapnic voluntary hyperpnea in asthmatic subjects

“…The reactions to both of the challenges are initiated by mast cell activation, as evident by the uniform excretion of PGD 2 , but, whereas the allergen challenge is an IgE-dependent specific mast cell activation, EVH activates mast cells through changes in osmolarity (2). The change in local tissue osmolarity is likely to induce excretion of PGE 2 from other cells in the airways and in particular from airway epithelial cells (14,16). In contrast, there was no increase in the excretion of PGF 2␣ , which is consistent with previous findings in plasma following exercise challenge (3) and again underscores the specificity of the pattern of excretion of lipid mediators.…”

Challenge of Isolated Sputum Cells Supports in vivo Origin of Intolerance Reaction to Aspirin/Non-Steroidal Anti-Inflammatory Drugs in Asthma

“…Lower levels of local biosynthesis of PGE 2 in AIA might therefore explain increased sensitivity to the inhibitory effects of NSAIDs. There are indications that the biosynthesis of PGE 2 in airway epithelium is catalysed by COX-1 [37], in line with the apparent tolerance to COX-2 inhibition in patients with AIA.…”