Androstenetriol immunomodulation improves survival in a severe trauma hemorrhage shock model.
BACKGROUND
Traumatic shock activates the hypothalamic-pituitary-adrenal axis (HPA) to mediate a cascade of defensive mechanisms that often include overwhelming inflammatory response and immunosuppression, which may lead to multiple organ failure. Androstenetriol (5 androstene, 3beta, 7beta, 17beta triol-AET) is a metabolite of dehydroepiandrosterone that markedly up regulates host immune response, prevents immune suppression, modulates inflammation and improves survival after lethal infections by pathogens and lethal radiation.


OBJECTIVE
AET-induced immune modulation will improve survival in a conscious rodent model of traumatic shock.


METHODS
A relevant traumatic shock rodent model that applies to both combat and civilian sectors was used. After creation of a midline laparotomy (soft tissue trauma), animals were hemorrhaged to a mean arterial pressure of 35-40 mm Hg. Resuscitation was initiated sixty minutes later with crystalloid fluid and packed red blood cells and animals were observed for two days. In a randomized and blinded fashion, AET or vehicle was administered subcutaneously at the beginning of resuscitation.


RESULTS
In the vehicle group 5 out of 16 animals survived, (31%). In contrast, 9 out of 13 animals who received AET survived (69%), (Fisher Exact Test p < 0.05). Survival in the AET treatment group was associated with reduced levels of IL-6, IL-10, and IL-18, and enhanced IFN-gamma and IL-2 levels.


CONCLUSIONS
: The results indicate that AET provides a significant protective effect and improves survival in a clinically relevant model of traumatic hemorrhagic shock. AET protective effects are associated with an elevation of Th1 and reduction of Th2 cytokines.
Marcu
Andreea C
AC
Virginia Commonwealth University Reanimation Engineering Shock Center (VCURES), Virginia Commonwealth University, Richmond, Virginia, USA.
Paccione
Kristin E
KE
Barbee
R Wayne
RW
Diegelmann
Robert F
RF
Ivatury
Rao R
RR
Ward
Kevin R
KR
Loria
Roger M
RM
D000737:Androstenols / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D007155:Immunologic Factors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012774:Shock, Traumatic / Q000188:drug therapy* / Q000503:physiopathology
C108492:5-androstene-3,7,17-triol; D000737:Androstenols; D007155:Immunologic Factors; D015850:Interleukin-6; D016209:Interleukin-8; D016753:Interleukin-10