LIPOXYGENASE STIMULATING EFFECTS OF HYDROXYLATED DOCOSAHEXAENOATES PRODUCED BY HUMAN PLATELETS

Human platelet suspensions are capable of lipoxygenating docosahexaeno ic acid (22:6n3) to an 11(S)-OH-, 14(S)-OH- or 17(S)-OH-22:6n3. The st ructure and stereochemical purity of these derivatives were confirmed by GC/MS and chiral phase LC analysis. The purified OH-22:6n3 position al isomers which are formed by human platelets were capable of inducin g a concentration-dependent contractile response in the guinea-pig lun g parenchymal strip at sub-micromolar concentrations. OH-22:6n3 may ac t in part through stimulation of leukotriene (LT) production as an inc rease in peptidyl-LT levels (LTC(4), LTD(4) and LTE(4)) occurred durin g the OH-22:6n3-induced contraction in this preparation. Both specific lipoxygenase inhibitors (caffeic acid, 20 uM and NDGA, 50 uM) and a L T receptor antagonist (FPL55712, 20 uM) significantly inhibited the co ntractile response. Moreover, the OH-22:6n3 positional isomers induced a concentration-dependent increase in LTB(4) and LTC(4) production in the guinea-pig chopped lung preparation. Other hydroxylated fatty aci ds and parent fatty acids which were tested (12-OH-20:4n6, 5-OH-20:4n6 , 12-OH-20:5n3, 20:5n3 and 22:6n3) did not significantly contract this airway smooth muscle preparation or alter LT production. The hydroxyl ated 22:6n3 metabolites may modulate airway smooth muscle function in. part through the release of peptidyl-LTs from the guinea-pig lung.