Published online before print August 8, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0406254

Received for publication April 6, 2006.
Revised May 5, 2006.
Accepted for publication June 23, 2006.

Article

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

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

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

^@ To whom correspondence should be addressed. 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 17-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 was observed after E2, flutamide, and E2 + flutamide administration, whereas neutrophil infiltration in lung and liver was only reduced significantly following E2 and E2 + flutamide administration. In addition, flutamide alone reduced lung MPO activity following T-H. 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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