GLUCOCORTICOID RECEPTOR BLOCKADE REVERSES POSTINJURY MACROPHAGE SUPPRESSION

Objectives: To study the effects of the stress-induced surge of endoge nous glucocorticoids on macrophage function and the role of inhibiting glucocorticoids with a receptor antagonist, mifepristone (RU 486). De sign: One hundred thirty female Swiss-Webster mice were randomly assig ned to either injury by femur fracture or uninjured anesthesia control in this intervention study. Setting: A university-based surgical labo ratory 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 Ou tcome Measures: Peritoneal macrophages were harvested 24 hours after t he injury. Macrophages were assayed for the stimulated (phorbol myrist ate acetate, 1 mu g/mL) production of superoxide anion, secretion of i nterleukin-6, tumor necrosis factor alpha, and prostaglandin E(2) in r esponse to endotoxin (lipopolysaccharide at 10 mu g/mL) and killing of Candida albicans. Results: Pretreatment with mifepristone significant ly prevented or reduced suppression of several macrophage functions fo llowing injury, including superoxide production and C albicans killing . Treatment after the injury preserved only C albicans. Mifepristone f ailed to block the increased secretion of prostaglandin E(2) after inj ury. Conclusion: Pretreatment with mifepristone before an injury preve nted 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 potentia l clinical applications of mifepristone trauma.