PB0519 - Age-Dependent Changes in Mortality and Biomarkers of Immunothrombosis in a Murine Model of Sepsis

Background: Although the incidence of sepsis increases with age in humans, most experimental models of sepsis utilize 2- to 3- month old mice (equivalent to approximately 20 years in humans), resulting in decreased scientific validity. Although sepsis is more lethal in an aged population, the mechanisms by which advanced age modulates the host response to severe infections are poorly understood.

Aims: To investigate the effects of aging on the host response to sepsis using fecal-induced peritonitis (FIP).

Methods: We used a diet-restriction model of aging in C57BL6 mice. We then induced sepsis in middle-aged (11 to 12 months) and young (2 to 3 months) mice using intraperitoneal injections of rat fecal slurry (0.75 mg/g). The mice were monitored every 4 hours for temperature and evidence of pain/distress until humane endpoint or until study endpoint (72h). In a separate experiment, the mice were culled at 4h, 8h, and 12h post-FIP to investigate the early response to sepsis. Data collected included bacterial counts in the blood and peritoneal cavity fluid (PCF) as well as immunothrombosis biomarkers.

Results: In the 72h survival study, middle-aged FIP mice exhibited a higher mortality rate, greater bacterial loads, and elevated levels of immunothrombosis biomarkers (increase in IL-6, thrombin-antithrombin, extracellular DNA, and reduction in protein C), compared to young FIP mice. In the time course study, middle-aged FIP mice exhibited greater bacterial loads in the PCF at 4h and 8h post-FIP and in the blood at 8h post-FIP, as well as an increase in IL-6 and a decrease in protein C compared to young FIP mice.

Conclusion(s): Middle-aged FIP mice exhibit a higher mortality rate, increase in disease severity, and an increase in pro-inflammatory and procoagulant biomarkers compared to young FIP mice. Understanding how age affects the host response to sepsis may improve our understanding of sepsis pathophysiology.