SEP-11: ANTI-ROS TREATMENT BY SPECIFIC MITOCHONDRIA-TARGETED ANTIOXIDANTS SKQ1 AND MITOTEMPO EXACERBATE MORTALITY IN THE ACUTE MURINE POLYMICROBIAL SEPSIS

INTRODUCTION:Altered mitochondrial function by excessive production of reactive oxygen species (ROS) has been considered an important factor in pathogenesis of organ failure in sepsis. METHODS:We investigated effects of two specific mitochondria-targeted antioxidants (SkQ1lipophilic; MitoTEMPOhydrophilic) on outcome, inflammatory response and organ homeostasis in a mouse model of cecal ligation and puncture (CLP) sepsis. 3-month old female CD-1 mice (n=90) were subjected to moderate-severity CLP, and treated intraperitoneally with SkQ1 (5nmol/kg), MitoTEMPO (50nmol/kg) or saline at 1 h, 12 h, 24 h, 36 h, 48 h post-CLP. We assessed 28-day survival, and circulating parameters over 0h-72 h post-CLP. Additional SkQ1/saline-treated CLP mice (n = 24) were sacrificed within the first 48 h for peritoneal lavage fluid (PLF) and spleen characterization. RESULTS:SkQ1 exacerbated mortality by 29% (to 67%; p = 0.04) and MitoTEMPO by 15% (to 53%; p = 0.24). CLP induced a systemic protracted cytokine release (IL-1β,-5,-6,-10,-12p70, CXCL-1, MCP-1, MIP-1α, IFN-γ, TNFα) and deregulation of organ function (urea, ALT, LDH, glucose), but antioxidant treatment failed to further modify them. Similar was true for CLP-induced lymphopenia/neutrophilia and NO-release in plasma (68 nM). Dying CLP mice had approximately 100-fold more CFUs in the spleen than survivors, but this effect was not SkQ1-related. In PLF, macrophage (CD11b+/F4/80+) (11%) and granulocyte (Ly6G+) (56%) counts and intra-/extracellular ROS (mean6629CMH[AU]/1181PPH[AU]) were similar, irrespectively of SkQ1 treatment. CONCLUSION:This CLP study shows that even refined, target-tailored antioxidant treatment is detrimental rather than beneficial. It is suggestive that in young female mice suffering from acute hyperinflammatory CLP sepsis, the negative role of mitochondrial ROS as the contributory factor to MODS is overestimated.