DIFFERENT METABOLIC PATHWAYS ASSOCIATED WITH TIME-DEPENDENT SEVERITY IN SEPTIC MICE

SENNA, CAMILA AGUSTINA; MUL FEDELE, MALENA LIS; AIELLO, IGNACIO; GOLOMBEK, DIEGO ANDRES; PALADINO, NATALIA

Congreso; Sociedad Argentina de Inmunología Reunión Anual 2023; 2023

Sociedad Argentina de Inmunología

Sepsis is a syndrome caused by a dysregulated host response to pathogens and represents the leading cause of death from infection. In murine models of endotoxemia, the mortality rate is largely dependent on the circadian system: Mice inoculated intraperitoneally with high doses of lipopolysaccharide (LPS; 20 mg/kg) at the end of the day show a higher mortality rate (~80%) compared to those inoculated at midnight (~30%), along with a greater inflammatory response and increased hypothermia. To study the mechanisms involved in this daily variation, we conducted a proteomic analysis on serum samples obtained 2 hours after the administration of LPS or vehicle (VEH) at the end of the day, ZT11, or at the middle of the night, ZT19 (ZT0: the time lights are turned on; ZT12: the time lights are turned off). We performed a two-way ANOVA analysis and observed that proteins increased at ZT19 are associated with glucose metabolism, energy utilization, and lipid metabolism (p < 0,05 for all proteins). On the other hand, differentially expressed proteins at ZT11 are involved in the inflammatory response, oxidative stress, and cell communication, migration, and adhesion (p < 0,05 for all proteins). Due to a higher food intake prior to LPS stimulation in animals inoculated at ZT19 than animals inoculated at ZT11 (p < 0,05), we administered glucose intraperitoneally 3 hours before the ZT11 stimulus to evaluate if the difference in prognosis is determined by glucose availability. However, we observed that this manipulation does not change the severity of sepsis (p n.s.). Furthermore, we evaluated blood glucose levels after stimulation at both time points and in the ANOVA test, we observed that animals exhibit hyperglycemia in response to LPS, within 2 hours post-stimulation, only at ZT11 (LPS ZT11 vs LPS ZT19, VEH ZT11 and VEH ZT19 p < 0,05). In conclusion, the prognosis of septic mice is not dependent on glucose availability prior to the stimulus. However, the increase in blood glucose in response to LPS at ZT11 could be signaling at the central level and/or promoting the activation of the inflammatory response, leading to greater severity in this condition.