The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis.
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-gamma), and IL-10 release and expression of androgen (AR) and estrogen receptors (ER)-alpha and -beta 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-gamma 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-gamma 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-alpha and -beta expression was observed in the vehicle-treated group after TH. In addition, AR and ER-beta mRNA expression was increased, whereas ER-alpha expression decreased in the vehicle-treated group after TH. ER-alpha expression decreased and ER-beta 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-beta mRNA expression was unaffected, whereas ER-alpha 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.
Schneider
C P
CP
Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, USA.
Nickel
E A
EA
Samy
T S
TS
Schwacha
M G
MG
Cioffi
W G
WG
Bland
K I
KI
Chaudry
I H
IH
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D047072:Aromatase Inhibitors; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics; D012151:Resuscitation; D018805:Sepsis / Q000150:complications / Q000401:mortality*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015996:Survival Rate; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014947:Wounds and Injuries / Q000150:complications / Q000188:drug therapy / Q000276:immunology*
D047072:Aromatase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D000735:Androstenedione; C014594:formestane