The pharmacologic modulation of the release of arachidonic acid metabolites from purified human lung mast cells.
Although cyclooxygenase and lipoxygenase inhibitors have been widely used in studies of allergic and inflammatory disorders, the effect of these agents has not been determined on mediators released from purified human lung mast cells. The release of histamine, prostaglandin D2, leukotriene C4, leukotriene B isomers, 5-hydroxyeicosatetraenoic acid (5-HETE), and free arachidonic acid (AA) from preparations of purified human lung mast cells (90 +/- 2% pure) prelabeled with 3H-AA as modified by indomethacin, eicosatriynoic acid (ETI), and diethylcarbamazine (DEC) was determined. Indomethacin (3 microM) markedly (greater than 90%) inhibited the anti-IgE- and ionophore A23187-induced release of PGD2 from these cells but had no effect on the release of histamine or other AA metabolites. Specifically, no increase in LTC production was noted, and no large amount of shunting of products into those produced by lipoxygenases was noted. The ETI, a lipoxygenase inhibitor in many systems, inhibited the release of histamine, PGD2, LTC, LTB isomers, 5-HETE, and free AA, all with an IC50 between 3 and 10 microM. The lack of specificity for lipoxygenase products together with a similar potency for inhibition of histamine release suggests that ETI may act at an early event in the activation process of these cells, apparently prior to the action of phospholipase(s), which releases AA from cellular stores. The DEC inhibited PGD2 release in purified mast cells and histamine release in pure and crude preparations of mast cells, both with IC50 values ranging from 1 to 3 mM. No specificity for enzymes responsible for the production of LTA4 was observed in these cells, unlike the results reported in other systems.(ABSTRACT TRUNCATED AT 250 WORDS)
D001091:Arachidonate Lipoxygenases; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors; D004049:Diethylcarbamazine / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D011863:Radioimmunoassay; D013189:SRS-A / Q000037:antagonists & inhibitors
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; C026603:5,8,11-eicosatriynoic acid; D016718:Arachidonic Acid; D001091:Arachidonate Lipoxygenases; D004049:Diethylcarbamazine; D007213:Indomethacin