Selectivity of cyclo-oxygenase inhibitors in human pulmonary epithelial and smooth muscle cells

Abstract

Selectivity of cyclo-oxygenase inhibitors in human pulmonary epithelial and smooth muscle cells. S.P. Range, L. Pang, E. Holland, A.J. Knox. #ERS Journals Ltd 2000. ABSTRACT: Cyclo-oxygenase (COX) inhibitors may have a role in reducing inflammation in asthma and other pulmonary diseases. COX inhibitors have different selectivities for the two COX isoenzymes (COX 1 and COX 2) which vary between purified enzyme and intact cell preparations. The relative selectivity of COX inhibitors has not been studied in human airway cells.A number of COX inhibitors in cultured human airway cells were compared which exclusively express either COX 1 (primary degree cultured human airway smooth muscle (HASM) cells) or COX 2 (A549 pulmonary epithelial cell-line) as measured by Western blotting. COX activity was assayed by prostaglandin (PG)E 2 production following 30 min incubation with 5 mM arachidonic acid.COX activity in both cell types was similar; HASM cells 92. -5 M for aspirin. Sodium valerate had no effect in either HASM or A549 cells. The COX 2:COX 1 selectivity ratio (COX 2 IC50/COX 1 IC50) was <0.0001 for nimesulide, 0.001 for NS398, 0.03 for flurbiprofen and 1.9 for indomethacin.In conclusion the present study has shown that cyclo-oxygenase inhibitors have a range of selectivities for cyclo-oxygenase 1 and cyclo-oxygenase 2 in intact human airway cells. The relative cyclo-oxygenase 2 selectivity of N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulphonamide and nimesulide may have implications for the treatment of asthma and other inflammatory pulmonary diseases. Recent studies have suggested that cyclo-oxygenase (COX) products may be involved in the pathophysiology of several pulmonary diseases: COX products have been implicated in the inflammation found in asthmatic airways, with different COX products exerting differential effects in different situations in vivo [1±3]. Inhaled indomethacin and aspirin protect against indirect bronchoconstrictor challenges in asthma [4,5] suggesting that release of constrictor prostaglandins such as prostaglandin (PG)D 2 and PGF 2a may contribute to the mechanisms of action of these stimuli. Under different circumstances COX products may have a protective role. PGE 2 has been shown to have a potential bronchoprotective role both in vitro [6,7] and in vivo [8,9]. Studies showing that oral indomethacin inhibits refractoriness to repeated bronchoconstriction challenge suggest that endogenous PGE 2 may be involved in this protective response [10,11]. A small number of patients with asthma exhibit aspirin sensitivity, whereby oral aspirin and other COX inhibitors produce bronchochoconstriction. This bronchoconstriction can be prevented by inhalation of PGE 2 [12,13]. Collectively these studies implicate COX products in several aspects of asthma pathophysiology, but it is clear that the responses to COX inhibition depend on the inhibitor studied, the route of administration, the circumstances of use and the type of patients studied. Studies in cultured airway smooth muscle cells in vitro have sug...

Intracellular signal transduction for migration and actin remodeling in vascular smooth muscle cells after sphingosylphosphorylcholine stimulation

“…Therefore, the effect of SB-203580 on cell migration may not be limited to the inhibition of p38. We failed to detect phosphorylation of p38 in GbaSM-4 cells treated with up to 50 mol/l indomethacin, a well-known inhibitor of cyclooxygenase (38) (Fig. 11A).…”

Interleukin-1β, Transforming Growth Factor-β 1 , and Bradykinin Attenuate Cyclic AMP Production by Human Pulmonary Artery Smooth Muscle Cells in Response to Prostacyclin Analogues and Prostaglandin E 2 by Cyclooxygenase-2 Induction and Downregulation of Adenylyl Cyclase Isoforms 1, 2, and 4

“…The concentration of NS398 we used selectively inhibits COX-2-mediated prostanoid generation by Ͼ90%. 48 Consistent with a major role for COX-2, NS398 abolished the effect of all three agents on prostanoid-mediated cAMP accumulation. The role of COX products was additionally established by showing that exogenously applied PGI 2 analogues, PGE 2 , or the COX substrate arachidonic acid mimicked the effect of IL-1␤, BK, and TGF-␤ 1 .…”

Modifications Produced by Indomethacin and <i>L</i>-NAME in the Effect of Ultralow-Dose Aspirin on Platelet Activity in Portal Hypertension

“…Although having a different mechanism of action to aspirin, it has a similar effect, since it is more active against COX-1 than COX-2 in bovine endothelial cells as in other models (IC 50 of COX-2/COX-1: 25 for aspirin and 40 for indomethacin in bovine endothelial cells). In human pulmonary epithelial smooth muscle cells, indomethacin had less selectivity for COX-1 than in other models [17] . In patients with PHT, indomethacin produced an increase in vascular resistance and a decrease in portal pressure [18] .…”