Although
androstenediol (adiol or 5-androstene-3beta,17beta-diol), a metabolite of
dehydroepiandrosterone (
DHEA), has protective effects following
trauma-
hemorrhage (T-H), it remains unknown whether administration of adiol has any salutary effects on the inflammatory response and outcome following a combined insult of T-H and
sepsis. Male rats underwent T-H
shock [mean arterial pressure (MAP) 40 mmHg for 90 min] followed by
resuscitation. Adiol (1 mg/kg body wt) or vehicle was administered at the end of
resuscitation.
Sepsis was induced by cecal
ligation and
puncture (CLP) at 20 h after T-H or
sham operation. Five hours after CLP, plasma and tissue samples were analyzed for
cytokines (IL-6 and IL-10), MPO,
neutrophil chemotactic factor (CINC-3), and liver injury (
alanine aminotransferase and
lactate dehydrogenase). In another group of rats, the gangrenous cecum was removed
at 10 h after CLP, the cavity was irrigated with warm saline and closed in layers, and mortality was recorded over 10 days. T-H followed by CLP produced a significant elevation in plasma
IL-6 and
IL-10 levels, enhanced neutrophil cell activation, and resulted in liver injury. Adiol administration prevented the increase in
cytokine production, neutrophil cell activation, and attenuated liver injury. Moreover, rats subjected to the combined insult, receiving vehicle or adiol, had a 50% and 6% mortality, respectively. Since adiol administration suppresses proinflammatory
cytokines, reduces liver damage, and decreases mortality after the combined insult of T-H and
sepsis, this agent appears to be a novel adjunct to fluid
resuscitation for decreasing T-H-induced septic complications and mortality.