title: Leptin Protects Against Mortality and Organ Dysfunction in A Two-Hit Trauma/Sepsis Model and is IL-6-Dependent.
abstract: 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.
  
  
  
  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 μg/g (leptin1) or 5 μg/g (leptin2)) subcutaneously and was observed for 8 days after induction of the first hit. Mortality, humoral, and cellular immune markers were determined.
  
  
  
  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-α and IL-6, not reaching statistical significance.
  
  
  
  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.
authors.affiliation: *Experimental Trauma Surgery, Department of Trauma Surgery, Rechts der Isar Hospital, Technical University of Munich, Munich, Germany †Department of Trauma Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Lukas Leopold
authors.initials: LL
authors.lastname: Negrin
authors.forename: Andreas
authors.initials: A
authors.lastname: Jahn
authors.forename: Martijn
authors.initials: M
authors.lastname: van Griensven
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D014947:Wounds and Injuries / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D020738:Leptin