Testosterone receptor blockade after hemorrhage in males. Restoration of the depressed immune functions and improved survival following subsequent sepsis

M. K. Angele, M. W. Wichmann, A. Ayala, W. G. Cioffi and I. H. Chaudry
Center for Surgical Research, Brown University School of Medicine, Providence, USA.

BACKGROUND: Recent studies suggest that androgen depletion by castration before hemorrhage has protective effects on cell-mediated immunity in male mice after soft tissue trauma and hemorrhagic shock. OBJECTIVE: To determine whether treatment with an androgen receptor blocker (eg, flutamide) after trauma-hemorrhage and sepsis has any salutary effects on cell-mediated immunity and on the survival of male animals under those conditions. DESIGN: Male C3H/HeN mice were either sham operated or subjected to hemorrhagic shock (mean [+/- SEM] blood pressure, 35 +/- 5 mm Hg for 90 minutes) followed by adequate fluid resuscitation (with shed blood and lactated Ringer solution). The animals then received either vehicle or 25-mg/kg body weight flutamide subcutaneously immediately after the resuscitation as well as 24 and 48 hours thereafter. At 48 hours after shock, sepsis was induced by cecal ligation and puncture. Sham-operated animals underwent laparotomy only. At 24 hours after cecal ligation and puncture, the animals were killed, blood was collected, and splenocytes and splenic macrophages were harvested to produce nonadherent and adherent cultures. Splenocytes were evaluated for splenocyte proliferation and interleukin 2 release, while interleukin 1 and interleukin 6 release were assayed in splenic macrophages. Plasma testosterone and corticosterone levels were also measured by radioimmunoassay. In a separate set of experiments, survival was measured over a period of 9 days after the induction of sepsis. RESULTS: Hemorrhage followed by sepsis produced a significant (P < .05) depression of splenocyte and macrophage functions in vehicle-treated animals. In contrast, animals treated with flutamide showed markedly improved immune functions, as evidenced by restoration of splenocyte proliferation, interleukin 2 release, splenic macrophage interleukin 1 release, and improvement of splenic macrophage interleukin 6 release. Plasma corticosterone levels were notably elevated while testosterone levels were depressed after hemorrhage and the induction of sepsis. The survival rate of the animals in the flutamide-treated group was also notably higher than the survival rate of animals in the vehicle-treated group subjected to hemorrhage and sepsis. CONCLUSION: The findings that flutamide not only markedly improves the depressed immune functions but also the survival of animals after hemorrhage and the induction of sepsis suggest that the short-term administration of androgen receptor blocker in males after trauma represents a safe and novel approach for preventing immune deficiency and decreasing the mortality rate from subsequent sepsis.