Androstenediol exerts salutary effects on chemokine response after trauma-hemorrhage and sepsis in mice

OBJECTIVES: The pathogenesis of multiple organ dysfunction syndrome and sepsis after polytrauma is related to the posttraumatic immune response and the associated release of inflammatory mediators. There exists a gender dimorphism in the posttraumatic host response. Sex steroids are believed to beneficially modulate the posttraumatic immune response. The specific effect of androstenediol on chemokines after trauma is unknown. We investigated whether the application of androstenediol has an effect on plasma chemokine levels and the associated remote organ damage in a two-hit mouse-model of trauma-hemorrhage, cecal ligation, and cecal puncture.

MATERIALS AND METHODS: Traumatic hemorrhage was induced followed by androstenediol application and volume resuscitation. Thereafter, androstenediol was given once daily in combination with a vehicle (Intralipid). The control group was injected with a solution containing only the vehicle at the same time points as the treatment groups' androstenediol applications. Sepsis was induced by cecal ligation and cecal puncture 48 hours afterward. Four hours after cecal ligation and cecal puncture, plasma measurements of chemokines were performed. Pulmonary infiltration by polymorphonuclear lymphocytes was measured by immunhistochemical staining and myeloperoxidase measurements were taken.

RESULTS: Application of androstenediol led to significantly decreased monocyte chemoattractant protein-1, monocyte chemoattractant protein-3, macrophage inflammatory protein-1α, and macrophage inflammatory protein-1β levels compared with the control animals after trauma-hemorrhage, cecal ligation, and cecal puncture (P < 0.05). Pulmonary infiltration and myeloperoxidase activity were significantly decreased in androstenediol-treated animals (P < 0.05).

CONCLUSION: Androstenediol modulates the immune response after trauma-hemorrhage, cecal ligation, and cecal puncture by reducing systemic chemokine levels, which are known to direct immune cells into the tissue possibly leading to organ damage. Androstenediol represents a potential therapeutic agent after major trauma in high-risk patients.