Characterizing the Protective Role of Pre‐Pubertal Status in Sepsis Outcomes

Epidemiologic data suggest that pre‐pubertal children exhibit a natural resistance to dying from SIRS/sepsis. We used an endotoxemia model of sterile sepsis to assess the effects of pubertal status on SIRS progression and outcome in mice. Following acute endotoxin injection (23μg/g i.p., all ~ 1:00 PM), pre‐pubertal mice (25 days old) exhibited significantly better survival than post‐pubertal mice (35 days old) over a 72 hour period (7 trials, n蠅50 per age group, p<0.0001).In addition to improved survival, pre‐pubertal mice exhibited increased weight loss at both early (2hr) and later (20hr) time points during endotoxemia (n=20, p=0.025; n蠅50, p<0.0001). Serum endotoxin concentrations were similar in both groups at 2 and 20hr, providing argument against differential absorption as a cause for better survival in the pre‐pubertal group. At 2hr, pre‐pubertal mice had higher absolute white blood cell counts (n蠅50, p=0.004). By 20hr, pre‐pubertal mice had similar white blood cell counts as post‐pubertal mice, but exhibited a lower percentage of lymphocytes (p=0.01) and higher percentages of monocytes (p=0.0001) and eosinophils (p=0.002). Analysis of peritoneal lavage fluid showed more Ly6G+Cd11b+ cells (granulocytes) in pre‐pubertal mice at 2 and 20hr (n=12, p=0.02; n>20, p=0.0001). Preliminary multiplex analysis revealed age‐dependent differences in the concentrations of certain serum cytokines (n=4 per age group). At 2hr, post‐pubertal mice had increased TNF‐α and IL‐10 while at 20hr, pre‐pubertal mice showed increased IL‐10, M‐CSF, and G‐CSF. These findings suggest that post‐pubertal mice have a greater initial inflammatory response to endotoxin while pre‐pubertal mice more efficiently promote later resolution. Support from DARPA