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Published online before print August 8, 2006

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(Journal of Leukocyte Biology. 2006;80:759-765.)
© 2006 by Society for Leukocyte Biology

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

Frank Hildebrand^*,1, William J. Hubbard^*, Mashkoor A. Choudhry^*, Bjoern M. Thobe^*, Hans-Christoph Pape and Irshad H. Chaudry^*,2

^* Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham Alabama; and
Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

² Correspondence: Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, GO94 Volker Hall, 1670 University Boulevard, Birmingham, AL 35294-0019. E-mail: Irshad.Chaudry{at}ccc.uab.edu

ABSTRACT

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 17ß-estradiol (E2; 50 µg/25 g), flutamide (625 µg/25 g), or E2 + flutamide. Four hours after resuscitation, plasma cytokine and chemokine (TNF-, IL-6, IL-10, IFN-, and MCP-1) concentrations and their release in vitro by hepatic and pulmonary tissue macrophages (M) 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-, IL-6, and MCP-1 concentrations under those conditions. This was accompanied by significantly decreased in vitro TNF- release by Kupffer cells after administration of E2, flutamide, or E2 + flutamide. The in vitro release of proinflammatory cytokines by alveolar M, 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.

Key Words: cytokines • liver • lungs • neutrophil infiltration • edema

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