Glucocorticoid Receptor Blockade Reverses Postinjury Macrophage Suppression

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Abstract
Objectives: To study the effects of the stress-induced surge of endogenous glucocorticoids on macrophage function and the role of inhibiting glucocorticoids with a receptor antagonist, mifepristone (RU 486). Design: One hundred thirty female Swiss-Webster mice were randomly assigned to either injury by femur fracture or uninjured anesthesia control in this intervention study. Setting: A university-based surgical laboratory and animal facility. Intervention: Injured mice were randomized to receive either the glucocorticoid receptor antagonist mifepristone (10 mg/kg by oral gavage) or its vehicle. Mifepristone or its vehicle were given either 2 hours before or 2 hours after the injury. Main Outcome Measures: Peritoneal macrophages were harvested 24 hours after the injury. Macrophages were assayed for the stimulated (phorbol myristate acetate, 1 μg/mL) production of superoxide anion, secretion of interleukin-6, tumor necrosis factor α, and prostaglandin E2in response to endotoxin (lipopolysaccharide at 10 μg/mL) and killing ofCandida albicans. Results: Pretreatment with mifepristone significantly prevented or reduced suppression of several macrophage functions following injury, including superoxide production andC albicanskilling. Treatment after the injury preserved onlyC albicans. Mifepristone failed to block the increased secretion of prostaglandin E2after injury. Conclusion: Pretreatment with mifepristone before an injury prevented suppression of several macrophage functions. Further studies are required on the effects of glucocorticoid inhibition on other aspects of the immune and metabolic responses to injury to define the potential clinical applications of mifepristone trauma. (Arch Surg. 1994;129:1227-1232)