Combination of dehydroepiandrosterone and orthovanadate administration reduces intestinal leukocyte recruitment in models of experimental sepsis

• DHEA reduced intestinal leukocyte adherence and improved capillary perfusion in experimental sepsis in male animals.
• DHEA reduced leukocyte adherence and improved capillary perfusion even more in ovariectomized females with sepsis.
• Combined treatment with DHEA and orthovanadate also reduced intestinal leukocyte adherence and improved capillary perfusion.
• In combination with orthovanadate, the dosage of DHEA can be halved, and still inhibit leukocyte adherence effectively.
• DHEA/orthovanadate administration may be useful in clinical sepsis to protect the intestinal microcirculation.

BackgroundDehydroepiandrosterone (DHEA) was shown to improve the immune function and survival in experimental sepsis. This study examined the effect of DHEA on intestinal leukocyte recruitment during experimental sepsis, considering factors of gender (male, female and ovariectomized female animals) and combined treatment using orthovanadate (OV) in two models of sepsis.Methodology/findingsMale rats underwent colon ascendens stent peritonitis (CASP) or endotoxemia. DHEA was administered after induction of experimental sepsis. Changes in leukocyte adherence and capillary perfusion (measured as intestinal functional capillary density — FCD) were assessed using intravital microscopy. While DHEA increased baseline leukocyte adherence in control animals, DHEA reduced leukocyte adherence and increased FCD in male animals with CASP. These effects were also observed in DHEA-treated ovariectomized female rats with CASP. Similarly, the administration of DHEA reduced the number of adherent leukocytes to intestinal venules by 30% in the endotoxemia model. The combined treatment of DHEA and OV significantly reduced adherence of leukocytes to intestinal venules and improved FCD.ConclusionsOur results indicate that DHEA is able to reduce intestinal leukocyte recruitment induced by experimental sepsis. Combination of DHEA with OV inhibits leukocyte adherence to intestinal endothelium, similar to what is achieved by the single administration of DHEA but with significantly improved FCD. These findings suggest a potential role for DHEA and OV in clinical sepsis.