OZONOLYSIS PRODUCTS OF MEMBRANE FATTY-ACIDS ACTIVATE EICOSANOID METABOLISM IN HUMAN AIRWAY EPITHELIAL-CELLS

When inhaled, ozone reacts at the airway luminal surface with unsatura ted fatty acids contained in the extracellular fluid and plasma membra ne to form an aldehyde and hydroxyhydroperoxide. The resulting hydroxy hydroperoxide degrades in aqueous systems to yield a second aldehyde a nd hydrogen peroxide (H2O2). Previously, we demonstrated that ozone ca n augment eicosanoid metabolism in bovine airway epithelial cells. To examine structure-activity relationships of ozone-fatty acid degradati on products on eicosanoid metabolism in human airway epithelial cells, 3-, 6-, and 9-carbon saturated aldehydes and hydroxyhydroperoxides we re synthesized and purified. Eicosanoid metabolism was evaluated by de termination of total H-3-activity release from confluent cells previou sly incubated with [H-3]arachidonic acid and by identification of spec ific metabolites with high performance liquid chromatography and radio immunoassay. The major metabolites detected were prostaglandin E(2), p rostaglandin F-2 alpha, and 15-hydroxy-eicosatetraenoic acid. The 9-ca rbon aldehyde, nonanal, in contrast to 3- or 6-carbon aldehydes, stimu lated release at concentrations greater than or equal to 100 mu M, sug gesting that the stimulatory effect increases with increasing chain le ngth. When tested under identical conditions, the 3-, 6-, and 9-carbon hydroxyhydroperoxides were more potent than the corresponding aldehyd es. Again, a greater effect was noted when the chain length was increa sed. One possible explanation for the increased potency of the hydroxy hydroperoxides over the aldehydes could be due to degradation of the h ydroxyhydroperoxide into H2O2 and aldehyde. We consider this an unlike ly explanation because responses varied with chain length (although ea ch hydroxyhydroperoxide would produce an equivalent amount of H2O2) an d because exposure to H2O2 alone or H2O2 plus hexanal produced a respo nse dissimilar to 1-hydroxy-1-hexanehydroperoxide. Inasmuch as these c ompounds are ozonolysis products of unsaturated fatty acids of the mem brane phospholipids, this study ascribes pathophysiologic significance to this chemical mechanism of ozone toxicity.