Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two-hit model of trauma-hemorrhage and sepsis.
Although administration of androstenediol (a metabolite of dehydroepiandrosterone) following trauma-hemorrhage (T-H) produces beneficial effects on inflammatory cytokines and organ function, it remains unknown whether this metabolite has any salutary effects in preventing alterations in immune cell cytokine production following a combined insult of T-H and sepsis. To examine this, male rats underwent laparotomy, hemorrhagic shock (mean BP 40 mmHg for 90 min) and resuscitation or sham operation. Androstenediol (1 mg/kg BW i.v.) or vehicle was administered at the end of resuscitation. Twenty hrs after T-H or sham operation, sepsis was induced by cecal ligation and puncture (CLP). Five hours thereafter, plasma cytokine levels and cytokine production of various immune cells were determined. In a separate set of experiments, survival was monitored for 10 days after the induction of sepsis. Administration of androstenediol markedly decreased plasma IL-6 and TNF-alpha levels following T-H and CLP. Furthermore, it prevented the increased production of IL-6 and TNF-alpha by Kupffer cells and alveolar macrophages and attenuated the decrease in IL-6 and TNF-alpha production by splenic macrophages; however, it had no significant effects on the depressed IL-6 and TNF-alpha production by PBMC following T-H and CLP. The depressed IL-2 and IFN-gamma production by splenocytes under those conditions was attenuated by the administration of androstenediol. Furthermore, survival rate following T-H and subsequent sepsis was improved by androstenediol treatment. Since androstenediol administration following T-H attenuated cytokine production and reduced mortality in a double-hit model of T-H and sepsis, this agent appears to be a novel and useful adjunct for maintaining the immune cell functions following T-H and for decreasing the mortality rate from subsequent susceptibility to sepsis.
Suzuki
Takao
T
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Shimizu
Tomoharu
T
Szalay
Laszlo
L
Choudhry
Mashkoor A
MA
Rue
Loring W
LW
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D045930:Anabolic Agents / Q000494:pharmacology; D015114:Androstenediol / Q000494:pharmacology*; D000818:Animals; D015551:Autoimmunity; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006470:Hemorrhage / Q000473:pathology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D018805:Sepsis / Q000473:pathology*
D045930:Anabolic Agents; D016207:Cytokines; D016753:Interleukin-10; D015114:Androstenediol