Effects of 17β‐estradiol and flutamide on inflammatory response and distant organ damage following trauma‐hemorrhage in metestrus females

We hypothesized that administration of androgen receptors antagonist flutamide following trauma‐hemorrhage (T‐H) in metestrus females will maintain immune function and reduce remote organ damage under those conditions. Female B57BL/J6 mice (metestrus state, 8–12 weeks old) underwent laparotomy and hemorrhagic shock (35.0±5.0 mmHg for 90 min) and then received 17β‐estradiol (E2; 50 μg/25 g), flutamide (625 μg/25 g), or E2 + flutamide. Four hours after resuscitation, plasma cytokine and chemokine (TNF‐α, IL‐6, IL‐10, IFN‐γ, and MCP‐1) concentrations and their release in vitro by hepatic and pulmonary tissue macrophages (MΦ) were determined by flow cytometry. Organ damage was assessed by edema formation (wet‐to‐dry weight ratio) and neutrophil infiltration [myeloperoxidase (MPO) activity]. Administration of E2, flutamide, or E2 + flutamide following T‐H resulted in a significant decrease in systemic TNF‐α, IL‐6, and MCP‐1 concentrations under those conditions. This was accompanied by significantly decreased in vitro TNF‐α release by Kupffer cells after administration of E2, flutamide, or E2 + flutamide. The in vitro release of proinflammatory cytokines by alveolar MΦ, however, was reduced significantly only by the addition of E2 or E2 + flutamide but not by the addition of flutamide. A significant decrease in pulmonary and hepatic edema formation as well as neutrophil infiltration in the lung was observed after E2, flutamide and E2 + flutamide administration. In contrast, hepatic neutrophil infiltration was only significantly reduced following E2 and E2 + flutamide administration. Thus, although flutamide does not produce synergistic, salutary effects with E2, its administration in females following T‐H also produces salutary effects on the immune and organ function, similar to E2 administration under those conditions.