Inhibition by methylprednisolone of zymosan-induced leukotriene synthesis in alveolar macrophages

Abstract

Alveolar-macrophage-derived 5-lipoxygenase metabolites of arachidonic acid (AA) are thought to be important mediators of lung inflammation and injury. Inhibition of AA metabolism may be an important anti-inflammatory mechanism of glucocorticoid (GC) action. In the present study, we have examined the effect of methylprednisolone (MP) on leukotriene (LT) B4 and LTC4 synthesis by cultured rat alveolar macrophages (AMs) stimulated with the proinflammatory particle zymosan. Zymosan stimulation resulted in the formation of LTB4 greater than thromboxane B2 (TxB2) greater than LTC4 as assessed by both high performance liquid chromatography and radioimmunoassay. Sixteen hours of pretreatment with 1 microM MP maximally inhibited synthesis of TxB2 by 76 +/- 4%, LTB4 by 83 +/- 3%, and LTC4 by 91 +/- 3%. The inhibition of eicosanoids was specific, as the sex hormones progesterone, testosterone, and beta-estradiol had no consistent effect. Inhibition was dose-dependent, with 50% inhibition of synthesis occurring at 10(-7) M for TxB2, but at 10(-8) M for both LTB4 and LTC4. Pretreatment with MP for only 1 h inhibited LTC4 production (42 +/- 3%) to a greater extent than either TxB2 (25 +/- 1%) or LTB4 (14 +/- 7%). These data indicate that MP significantly and substantially inhibits zymosan-induced LTB4 and LTC4 synthesis. Furthermore, the greater degree, greater potency, and faster onset of action for MP inhibition of LT synthesis than of TxB2 synthesis suggest the possibility that MP may exert postphospholipase effect(s) on LT synthesis. These results support the possibility that modulation of AM arachidonate metabolism may represent an important anti-inflammatory mechanism of GC action in the lung.