Abstract 14066: O -GlcNAc Levels Stimulation is a New Potential Therapeutic Strategy at the Early Phase of Septic Shock in the Young

Abstract

Background: We have shown that increase in O -GlcNAc levels, a post-translational modification involved in the stress response, at the early phase of septic shock in adult (84 days old rats) is a potential new therapeutic strategy. Most studies focus in adults while the population most affected by septic shock, young children, is rarely studied. Considering that O- GlcNAc levels are higher in the young, the impact of O- GlcNAc on septic shock in the young should be tested. Purpose: Evaluate if O- GlcNAc stimulation could improve sepsis outcomes in young. Methods: Endotoxemic shock was induced in 28 days old rats with an i.v. injection of saline (CTRL, n=10) or LPS (O111:B4, 20mg.kg -1 - LPS, n=9). 1 hour after LPS rats were randomly assigned to no therapy (LPS), fluidotherapy (saline, 10ml.kg -1 - LPS+R, n=10) ± NButGT (10 mg.kg -1 - NButGT, n=11) to increase O- GlcNAc levels. 2 hours later, physiological functions and markers of severity were measured and used in adapted Pediatric RISk of Mortality score (PRISM score). The impact of treatment on survival was evaluated on n=16 per group. Mass spectrometry (MS) study was performed to identify O -GlcNAcylated proteins. Results: LPS induce a shock (mean arterial pressure (MAP): CTRL: 67.2 ± 1.9; LPS: 50.7 ± 2.1; mmHg; p<0.05), alter biological parameters (lactates: CTRL: 3.92 ± 0.26; LPS: 6.42 ± 0.45; mmol.l -1 ; pH: CTRL: 7.27 ± 0.02; LPS: 7.15 ± 0.02; p<0.05), PRISM score (p<0.05) and is associated with multi organs dysfunction (troponin T: CTRL: 19.7 ± 4.0; LPS: 45.4 ± 11.4; ng.l -1 ; creatinine: CTRL: 15.9 ± 1.5; LPS: 25.3 ± 2.6; μmol.l -1 ; p<0.05). LPS+R has no beneficial effect while NButGT improves MAP (p<0.05), PRISM score (p<0.05) and the median survival (NButGT: 36.0; LPS+R: 13.65; hours; p<0.001) compared to LPS+R treatment. MS highlight important variations of O- GlcNAcylation particularly that of mitochondrial proteins. Conclusions: Despite higher O- GlcNAc levels, we demonstrate that O- GlcNAc stimulation is also a potential new therapeutic strategy for septic shock in young. Our results show that it is the difference between the basal levels and the post-stimulation levels which induces a protection against sepsis. Proteins identify by MS will need to be specifically studied to decipher their impact in septic shock.