The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis

Christian P. Schneider, Eike A. Nickel, T. S.Anantha Samy, Martin G. Schwacha, William G. Cioffi, Kirby I. Bland, Irshad H. Chaudry

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Studies have shown that immune responses are depressed in male mice, but not in proestrus females after trauma-hemorrhage (TH), resulting in increased mortality from subsequent sepsis in male mice compared with female mice. These gender-specific alterations in immune function are believed to be due to differences in sex steroid levels. Aromatase is a key enzyme in the sex steroid biosynthesis. Although earlier studies have shown that aromatase inhibitors prevent thymic atrophy in aged male rats, it remains unknown whether the use of 4-hydroxy-androstenedione (4-OHA) after TH in male mice has any salutary effects on the depressed immune responses. Male C3H/HeN mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (30 ± 5 mmHg for 90 min) followed by adequate fluid resuscitation. 4-OHA (5 mg/kg) or vehicle was administrated s.c. just before resuscitation. At 2 h after resuscitation, the mice were killed, and spleens were harvested. Splenocyte proliferation, interleukin (IL-2), interferon (IFN-γ), and IL-10 release and expression of androgen (AR) and estrogen receptors (ER)-α and -β by immunoblot and reverse transcription-polymerase chain reaction (RT-PCR) were assessed. In another group, sepsis was induced by cecal ligation and puncture (CLP) 3 days after resuscitation, and survival was measured over a period of 10 days. A significant decrease in splenocyte proliferation, IL-2, and IFN-γ release and increased release of IL-10 were observed in vehicle-treated mice. Animals treated with 4-OHA showed increased splenocyte proliferation, IL-2, and IFN-γ release, and decreased IL-10 release. Immunoblot analysis showed decreased expression of the cytosolic AR, but no significant difference in the cytosolic and nuclear ER-α and -β expression was observed in the vehicle-treated group after TH. In addition, AR and ER-β mRNA expression was increased, whereas ER-α expression decreased in the vehicle-treated group after TH. ER-α expression decreased and ER-β expression increased in the nucleus of 4-OHA treated mice as determined by immunoblot. There was no difference in the cytosolic AR expression in the 4-OHA-treated group after TH. AR and ER-β mRNA expression was unaffected, whereas ER-α expression increased under such conditions. In additional groups, the increased mortality rate after TH and subsequent sepsis was significantly reduced by 4-OHA treatment. Thus, 4-OHA seems to be a novel and useful adjunct for restoring the depressed immune functions in males after TH and for decreasing mortality rates from subsequent sepsis.

Original languageEnglish (US)
Pages (from-to)347-353
Number of pages7
JournalShock
Volume14
Issue number3
DOIs
StatePublished - Sep 2000
Externally publishedYes

Keywords

  • Gender
  • Hemorrhagic shock
  • IFN-γ
  • IL-2
  • Immune depression
  • Lymphocytes
  • Sex steroid receptors

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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