Thioredoxin in human and experimental sepsis

INTRODUCTION:Thioredoxin (TRX) is assumed to be beneficial in acute inflammatory diseases because of its potent antioxidant properties and an inhibitory effect on neutrophil evasion into sites of inflammation. OBJECTIVE:To compare plasma levels of thioredoxin in septic patients and to investigate the role of thioredoxin in a polymicrobial septic mouse model. DESIGN AND INTERVENTIONS:A combined single-center noninterventional clinical observation study and randomized controlled experimental investigation. SETTING:Intensive care unit of a university hospital and laboratories of four university hospitals. MEASUREMENTS AND MAIN RESULTS:To evaluate the role of TRX in sepsis, we measured TRX in plasma of septic patients and compared its levels in survivors and patients who did not survive sepsis. In addition, we examined the effect of neutralization of endogenous TRX as well as of treatment with recombinant TRX in a mouse peritonitis model of cecal ligation and puncture (CLP). We found that the serum plasma levels of TRX were significantly higher in patients with sepsis compared with healthy individuals. Furthermore, nonsurvivors showed even higher TRX levels than survivors of sepsis. The CLP septic mouse model revealed that neutralization of endogenous TRX impaired survival of septic mice, whereas treatment with recombinant TRX after CLP strongly enhanced the survival of mice. CONCLUSIONS:Our results therefore demonstrate a critical role for TRX in the septic inflammatory response and suggest TRX as a potential therapeutic target for septic shock.