Ozonolysis Products of Membrane Fatty Acids Activate Eicosanoid Metabolism in Human Airway Epithelial Cells

Abstract

When inhaled, ozone reacts at the airway luminal surface with unsaturated fatty acids contained in the extracellular fluid and plasma membrane to form an aldehyde and hydroxyhydroperoxide. The resulting hydroxyhydroperoxide degrades in aqueous systems to yield a second aldehyde and hydrogen peroxide (H2O2). Previously, we demonstrated that ozone can augment eicosanoid metabolism in bovine airway epithelial cells. To examine structure-activity relationships of ozone-fatty acid degradation products on eicosanoid metabolism in human airway epithelial cells, 3-, 6-, and 9-carbon saturated aldehydes and hydroxyhydroperoxides were synthesized and purified. Eicosanoid metabolism was evaluated by determination of total 3H-activity release from confluent cells previously incubated with [3H]arachidonic acid and by identification of specific metabolites with high performance liquid chromatography and radioimmunoassay. The major metabolites detected were prostaglandin E2, prostaglandin F2 alpha, and 15-hydroxyeicosatetraenoic acid. The 9-carbon aldehyde, nonanal, in contrast to 3- or 6-carbon aldehydes, stimulated release at concentrations > or = 100 microM, suggesting that the stimulatory effect increases with increasing chain length. When tested under identical conditions, the 3-, 6-, and 9-carbon hydroxyhydroperoxides were more potent than the corresponding aldehydes. Again, a greater effect was noted when the chain length was increased. One possible explanation for the increased potency of the hydroxyhydroperoxides over the aldehydes could be due to degradation of the hydroxyhydroperoxide into H2O2 and aldehyde. We consider this an unlikely explanation because responses varied with chain length (although each hydroxyhydroperoxide would produce an equivalent amount of H2O2) and because exposure to H2O2 alone or H2O2 plus hexanal produced a response dissimilar to 1-hydroxy-1-hexanehydroperoxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway epithelial cell responses to ozone injury.

“…This, in part, results from augmented bioactive lipid mediator release from both resident and migratory cells, with elevations present in pro-inflammatory eicosanoid (e.g., leukotriene B4 or prostaglandin F2Q). As noted previously, ozone activates eicosanoid metabolism in airway epithelial cells (17,36).…”

Hazardous air pollutants and asthma.

“…These intermediates are HAPs and can activate mediator release from human airway epithelial cells, thereby linking the biochemical outcomes of ozone with these compounds (118,119). The source of these types of HAPs is mixed.…”

Detection of Aldehydes in Bronchoalveolar Lavage of Rats Exposed to Ozone

“…Third, we have detected significant increases in the amounts of aliphatic alde- hydes in the bronchoalveolar lavage of rats following ozone exposure (Cueto et al, , 1994. Finally, oxidized lipids are known to act as messengers of a variety of cellular signals, including the inflammatory response (Pryor et al, 1995b;Wright et al, 1994b;Leikauf et al, 1993Leikauf et al, , 1995Stremler et al, 1989;Zimmerman et al, 1995).…”

“…Further work on LOP should involve the demonstration that LOP signal the release of traditional inflammatory factors such as eicosanoids (Leikauf et al, 1993) and plateletactivating factor (Wright et al, 1994a;Pryor et al, 1995a). In addition, it is possible that LOP alter the activity of key enzymes in the lung that control eicosanoid and nitric oxide synthesis.…”

“…Therefore many of the pulmonary and all of the nonpulmonary effects of ozone must arise from the production of initial ozonation products as ozone enters the lung^air interface and the subsequent reactions of these initial ozonation products. The initial ozonation products are known to include molecules formed from the ozonation of lipids (Goldstein and Balchum, 1967;Goldstein etal, 1969;Balchum etal., 1971;Mudd and Freeman, 1977;Pryor et al, 1976;Leikauf et al, 1993). These primary reaction products then relay the effects of ozone to deeper tissue strata (Pryor, 1993;Goldstein and Balchum, 1967;Pryor et al, 1995b;Leikauf et al, 1995;Wright etal., 1994b).…”