LEPTIN PROTECTS AGAINST MORTALITY AND ORGAN DYSFUNCTION IN A TWO-HIT TRAUMA/SEPSIS MODEL AND IS IL-6-DEPENDENT

Introduction: Leptin is thought to play an important role in the regulation of the immune system. In patients, leptin is inversely proportional to interleukin-6 (IL-6) levels. Thus, the objective of our study was to evaluate a dose-dependent therapeutic impact of leptin with possible IL-6-dependency on immune actions and outcome in a trauma/sepsis model. Materials and Methods: Sixty-nine wild-type and 63 IL-6(-/-) mice were subdivided into three groups: trauma/sepsis group (first hit: femur fracture and hemorrhage; second hit: cecal ligation and puncture 2 days later), trauma group (first hit and laparotomy), sham group (laparotomy only). Each group received vehicle or leptin (2.5 mg/g (leptin1) or 5 mg/g (leptin2)) subcutaneously and was observed for 8 days after induction of the first hit. Mortality, humoral, and cellular immune markers were determined. Results: We revealed a dose-dependent anti-inflammatory effect of exogenous leptin in the sepsis groups and to some extent a pro-inflammatory effect in the sham groups. Leptin administration resulted in a decreased mortality in septic wild-type mice (trauma/sepsis vehicle group: 36.4%, trauma/sepsis leptin1 group: 25%, trauma/sepsis leptin2 group: 0%) and in an increased mortality in septic IL-6(-/-) mice (53.8%, 83.4%, 100%). All mice of the trauma groups and sham groups survived. In wild-type trauma/sepsis mice, exogenous leptin led to increased levels of CD4(+) and CD8(+) in the spleen, and a less pronounced type IV hypersensitivity (P <= 0.039). Furthermore, it decreased the levels of tumor necrosis factor-alpha and IL-6, not reaching statistical significance. Conclusions: Due to the fact that leptin administration to traumatized and septic mice seems to have a positive effect on their outcome via IL-6 and does not negatively impact their medical condition if applied preventively, leptin might be a therapeutic agent for the prevention, or treatment of sepsis-related detrimental outcome after initial trauma.