Female sex hormones regulate macrophage function after trauma-hemorrhage and prevent increased death rate from subsequent sepsis.
OBJECTIVE
To determine whether reduction of circulating female sex hormones by ovariectomy causes suppression of macrophage (Mphi) function after trauma-hemorrhage and increases susceptibility to subsequent sepsis.


BACKGROUND
Studies indicate that immune functions are markedly depressed in males but not in proestrus females after trauma-hemorrhage. Although male sex steroids are immunosuppressive, it remains unknown whether female sex hormones are immunoprotective after trauma-hemorrhage.


METHODS
Circulating female sex hormones were reduced by ovariectomy of 8-week-old female CBA/J mice. Two weeks afterward, ovariectomy and proestrus sham-ovariectomy mice were subjected to laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (35 +/- 5 mm Hg for 90 minutes, then resuscitated) or sham operation. Two hours afterward, splenic and peritoneal Mphi and Kupffer cells were isolated and cytokine production was assessed. In a second series of experiments, animals were subjected to sepsis by cecal ligation and puncture at 24 hours after trauma-hemorrhage or sham operation, and survival was assessed.


RESULTS
Release of interleukin-1 and interleukin-6 by splenic and peritoneal Mphi from proestrus mice was maintained after trauma-hemorrhage, whereas release of interleukin-1 and interleukin-6 by Mphi from ovariectomized mice was depressed by approximately 50%. In contrast, trauma-hemorrhage resulted in a fourfold increase of Kupffer cell release of tumor necrosis factor-alpha in ovariectomized females and a fivefold increase in plasma concentrations of tumor necrosis factor-alpha. Release of tumor necrosis factor-alpha and plasma concentrations were unchanged in proestrus mice under such conditions. When proestrus and ovariectomized animals were subjected to sepsis by cecal ligation and puncture at 24 hours after trauma-hemorrhage or sham operation, ovariectomized mice had a significantly higher death rate than proestrus mice.


CONCLUSIONS
These findings suggest that female sex hormones play a critical role in maintaining immune responses after trauma-hemorrhage by suppressing the elaboration of tumor necrosis factor-alpha and prevent the increased lethality from subsequent sepsis. Thus, female sex hormones may be a useful adjunct in preventing trauma-induced immunodepression and increased susceptibility to subsequent sepsis.
Knöferl
Markus W
MW
Center for Surgical Research, Department of Surgery, University of Alabama at Birmingham, 35294-0019, USA.
Angele
Martin K
MK
Diodato
Michael D
MD
Schwacha
Martin G
MG
Ayala
Alfred
A
Cioffi
William G
WG
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004958:Estradiol / Q000097:blood; D005260:Female; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D006470:Hemorrhage / Q000276:immunology*; D007165:Immunosuppression Therapy; D015850:Interleukin-6 / Q000097:blood; D007378:Interleukins / Q000097:blood; D007728:Kupffer Cells / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008808:Mice, Inbred CBA; D010052:Ovariectomy; D011359:Proestrus; D011863:Radioimmunoassay; D018805:Sepsis / Q000276:immunology / Q000401:mortality*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014947:Wounds and Injuries / Q000276:immunology*
D016207:Cytokines; D012739:Gonadal Steroid Hormones; D015850:Interleukin-6; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol