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.