Journal of Leukocyte Biology 48:81-88 (1990) © 1990 Wiley-Liss, Inc. Glucocorticoids Fail to Inhibit Arachidonic Acid Metabolism Stimulated by Hydrogen Peroxide in the Alveolar Macrophage Peter H.S. Sporn, Teresa M. Murphy, and Marc Peters-Golden Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan and Veterans Administration Medical Centers, Ann Arbor We have previously demonstrated that the biologically important oxidant hydrogen per- oxide (H202) triggers release and metabolism of arachidonic acid (AA) in the alveolar macrophage (AM). In this study, we evaluated the ability of glucocorticoids to inhibit rat AM AA metabolism stimulated by H2O2, as compared to the particulate zymosan. Meth- ybprednisobone and other glucocorticoids failed to significantly inhibit release of AA stimulated by H2O2, while markedly reducing AA release in response to zymosan. Simi- larly, methylprednisobone only weakly inhibited synthesis of thromboxane (Tx)B2 stimu- bated by H202, while inhibiting zymosan-induced eicosanoid synthesis to a marked de- gree. On the other hand, the phospholipase inhibitor mepacrine strongly Inhibited AA release and TxB2 formation stimulated by both H202 and zymosan, indicating that H202- induced AA metabolism is indeed susceptible to pharmacologic inhibition. The failure of glucocorticoids to inhibit AA metabolism stimulated by H2O2 in the AM may in part explain their inability to ameliorate oxidant-mediated lung inflammation and injury. Key words: oxidants, zymosan, methybprednisolone, mepacrine, thromboxane, lung in- flammation INTRODUCTION Glucocorticoid steroids are efficacious in the treatment of a variety of immune and inflammatory disorders af- fecting the lung and other organs. The ability of giuco- corticoids to inhibit the phospholipase-catalyzed release of arachidonic acid (AA), and thereby its subsequent metabolism to bioactive eicosanoids, is believed to rep- resent an important mechanism of their anti-inflamma- tory action [ 1-3] . The alveolar macrophage (AM), which plays a central role in regulating immune and infiamma- tory processes in the lung, is enriched in AA [4] and has the capacity to synthesize substantial quantities of ci- cosanoids via both the cyclooxygenase and the 5-lipoxy- genase pathways [5-7]. In previous studies, we have examined the effects of giucocorticoids on AA metabo- lism in AMs challenged with the agonists zymosan and calcium ionophore A23187. Our studies demonstrated that giucocorticoids inhibit AA release and eicosanoid synthesis stimulated by the particulate zymosan in the rat AM [8,9] and by the soluble stimulus A23i87 in the human AM [10]. Inhibition by glucocorticoids of ci- cosanoid synthesis stimulated by zymosan in the human AM has also been reported [1 1]. Glucocorticoid inhibi- tion of AA release and metabolism has similarly been documented in a wide variety of other cells and tissues [1-3,12-171. Interestingly, glucocorticoids fail to ameliorate, or ac- tualiy worsen, lung inflammation and injury in animals exposed to hyperoxia [ 1 8-20] or the chemical oxidant paraquat [21]. Recently, we have demonstrated that non- cytolytic doses of hydrogen peroxide (H2O2), a key me- diator of oxidant lung injury [22-25], have the capacity to trigger the release of AA and its metabolism to cy- clooxygenase (but not 5-iipoxygenase) products in the rat AM [26,27]. In the current study, we have investigated the ability of glucocorticoids to regulate rat AM AA metabolism stimulated by this biologically important ox- idant. Our results indicate that, in contrast to AA metab- olism stimulated by the classical agonist zymosan. glu- cocorticoids fail to inhibit AA release and eicosanoid synthesis triggered by H.,O,. Received September 25. 1989: accepted November 14. 1989. Reprint requests: Peter H.S. Sporn. Division of Pulmonary and Crit- ical Care Medicine. 3916 Taubman Center. University of Michigan Medical Center. Ann Arbor. Ml 481()9-0360.