Effects of 17beta-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 17beta-estradiol (E2; 50 microg/25 g), flutamide (625 microg/25 g), or E2 + flutamide. Four hours after resuscitation, plasma cytokine and chemokine (TNF-alpha, IL-6, IL-10, IFN-gamma, and MCP-1) concentrations and their release in vitro by hepatic and pulmonary tissue macrophages (M Phi) 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-alpha, IL-6, and MCP-1 concentrations under those conditions. This was accompanied by significantly decreased in vitro TNF-alpha release by Kupffer cells after administration of E2, flutamide, or E2 + flutamide. The in vitro release of proinflammatory cytokines by alveolar M Phi, 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.
Hildebrand
Frank
F
Department of Surgery, University of Alabama at Birmingham, AL 35294-0019, USA.
Hubbard
William J
WJ
Choudhry
Mashkoor A
MA
Thobe
Bjoern M
BM
Pape
Hans-Christoph
HC
Chaudry
Irshad H
IH
D000818:Animals; D018932:Chemokine CCL2 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005485:Flutamide / Q000008:administration & dosage*; D006470:Hemorrhage / Q000188:drug therapy* / Q000276:immunology; D007249:Inflammation; D007279:Injections, Subcutaneous; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology*; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008686:Metestrus / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D009195:Peroxidase / Q000276:immunology; D012680:Sensitivity and Specificity
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D004958:Estradiol; D005485:Flutamide; D009195:Peroxidase