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

Harrington LS, Lucas R, McMaster SK, Moreno L, Scadding G, Warner TD, Mitchell JA - FASEB J. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Cardiac Medicine, NHLI, Imperial College, Dovehouse St., London SW3 6LY, UK.

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.

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Effect of NSAIDs on bronchoconstrictions induced by U46619 (A–C) or ACh (D–F) in airway tissue from COX-1−/− mice. The effects of the following NSAIDs were tested on constrictor responses to U46619 or ACh of naproxen (10−5 M), diclofenac (10−5 M), and ibuprofen (10−4 M). Responses are means ± se for n = 4 or 5 experiments; 2-way ANOVA. ns, nonsignficant difference (P>0.05).
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Figure 4: Effect of NSAIDs on bronchoconstrictions induced by U46619 (A–C) or ACh (D–F) in airway tissue from COX-1−/− mice. The effects of the following NSAIDs were tested on constrictor responses to U46619 or ACh of naproxen (10−5 M), diclofenac (10−5 M), and ibuprofen (10−4 M). Responses are means ± se for n = 4 or 5 experiments; 2-way ANOVA. ns, nonsignficant difference (P>0.05).

Mentions: Bronchi from wild-type mice contained predominantly COX-1 immunoreactivity (Fig. 1; 87.2±9.6% of COX-1 positive control; n=4). COX-1 immunoreactivity persisted in tissue from COX-1−/− mice (86.5±18.3% of COX-1 positive control; n=3), most likely explained by the presence in tissue from these mice of a nonfunctional protein product (7). No COX-2 immunoreactivity was detected in bronchi from either wild-type or COX-1−/− mice (Fig. 1). Bronchi from wild-type or COX-1−/− mice contracted in response to increasing concentrations of U46619 (10−9 to 3×10−6 M; Fig. 2A) or acetylcholine (10−8 to 3×10−4M; Fig. 2B). For both agonists, responses in bronchi from COX-1−/− mice were increased compared to those in bronchi taken from wild-type mice. Pretreatment of bronchi from wild-type animals with naproxen (10−4 M), diclofenac (10−5 M), or ibuprofen (10−5 M) increased bronchoconstrictor responses to both U46619 (Fig. 3A–C) and acetylcholine (Fig. 4A–C). In contrast, pretreatment of bronchi from COX-1−/− mice with ibuprofen or naproxen had no significant effect on contractions induced by either U46619 (Fig. 3D–F) or acetylcholine (Fig. 4D–F).


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

Harrington LS, Lucas R, McMaster SK, Moreno L, Scadding G, Warner TD, Mitchell JA - FASEB J. (2008)

Effect of NSAIDs on bronchoconstrictions induced by U46619 (A–C) or ACh (D–F) in airway tissue from COX-1−/− mice. The effects of the following NSAIDs were tested on constrictor responses to U46619 or ACh of naproxen (10−5 M), diclofenac (10−5 M), and ibuprofen (10−4 M). Responses are means ± se for n = 4 or 5 experiments; 2-way ANOVA. ns, nonsignficant difference (P>0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691413&req=5

Figure 4: Effect of NSAIDs on bronchoconstrictions induced by U46619 (A–C) or ACh (D–F) in airway tissue from COX-1−/− mice. The effects of the following NSAIDs were tested on constrictor responses to U46619 or ACh of naproxen (10−5 M), diclofenac (10−5 M), and ibuprofen (10−4 M). Responses are means ± se for n = 4 or 5 experiments; 2-way ANOVA. ns, nonsignficant difference (P>0.05).
Mentions: Bronchi from wild-type mice contained predominantly COX-1 immunoreactivity (Fig. 1; 87.2±9.6% of COX-1 positive control; n=4). COX-1 immunoreactivity persisted in tissue from COX-1−/− mice (86.5±18.3% of COX-1 positive control; n=3), most likely explained by the presence in tissue from these mice of a nonfunctional protein product (7). No COX-2 immunoreactivity was detected in bronchi from either wild-type or COX-1−/− mice (Fig. 1). Bronchi from wild-type or COX-1−/− mice contracted in response to increasing concentrations of U46619 (10−9 to 3×10−6 M; Fig. 2A) or acetylcholine (10−8 to 3×10−4M; Fig. 2B). For both agonists, responses in bronchi from COX-1−/− mice were increased compared to those in bronchi taken from wild-type mice. Pretreatment of bronchi from wild-type animals with naproxen (10−4 M), diclofenac (10−5 M), or ibuprofen (10−5 M) increased bronchoconstrictor responses to both U46619 (Fig. 3A–C) and acetylcholine (Fig. 4A–C). In contrast, pretreatment of bronchi from COX-1−/− mice with ibuprofen or naproxen had no significant effect on contractions induced by either U46619 (Fig. 3D–F) or acetylcholine (Fig. 4D–F).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Cardiac Medicine, NHLI, Imperial College, Dovehouse St., London SW3 6LY, UK.

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.

Show MeSH
Related in: MedlinePlus