15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and rofecoxib

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Aspirin; Asthma; Bronchi; Bronchoconstriction; Bronchoconstrictor Agents; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Hypersensitivity; Humans; Lactones; Membrane Proteins; Mice; Mice, Knockout; Respiratory Mucosa; Sulfones; Vasoconstrictor Agents

Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Carotid Artery Injuries; Carotid Artery, Common; Cell Division; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Endothelium, Vascular; Epoprostenol; Humans; Isoenzymes; Lactones; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Naphthalenes; Platelet Activation; Platelet Aggregation; Propionates; Prostaglandin-Endoperoxide Synthases; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfones; Tetrahydronaphthalenes; Thromboxane A2; Tunica Intima