Acute increases of O ‐GlcNAcylation reduces sepsis‐associated mortality (837.8)

The post‐translational modification of proteins by O ‐GlcNAcylation ( O ‐GlcNAc) is highly dynamic and modulates cell‐signaling processes. Acute increases in O ‐GlcNAc levels reduce migration of inflammatory cells and the release of pro‐inflammatory mediators, important events in sepsis caused by bacterial infection or multiple non‐infectious causes. This study tested the hypothesis that acute increases of O ‐GlcNAc levels reduce mortality and inflammatory processes in experimental models of sepsis. C57/BL6 mice were used in experimental sepsis protocols cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)‐induced severe and mild sepsis. Glucosamine treatment (300mg/Kg, i.v. 30 min. before the sepsis induction) acutely increased vascular and spleen O ‐GlcNAc levels and increased survival of mice with LPS‐induced sepsis (50%) and CLP sepsis (40%). In mice with LPS‐induced sepsis, glucosamine also reduced neutrophil migration to the peritoneal cavity (severe LPS sepsis, p <0.05; mild LPS sepsis, p <0.01), myeloperoxidase (MPO) activity of lung neutrophils (severe LPS sepsis, p <0.01; mild LPS sepsis, p <0.001) and aortic IL‐1beta mRNA expression (mild LPS sepsis, p <0.01). In the CLP model, glucosamine reduced MPO activity of lung neutrophils (p<0.05). These results show that glucosamine‐induced acute increases of O ‐GlcNAc levels increase survival in the CLP and LPS experimental models of sepsis. This study suggests that the O ‐GlcNAc pathway represents a potential target in sepsis‐related systemic inflammatory responses. Grant Funding Source : CNPq, CAPES and FAPESP