Immune suppression is known to occur during
sepsis. Endotoxin tolerance is considered a mechanism of immune suppression in
sepsis. However, the timing and serial changes in endotoxin tolerance have not been fully investigated. In this study, we investigated serial changes in endotoxin tolerance in a polymicrobial
sepsis model. Herein, we used a rat model of fecal slurry polymicrobial
sepsis. After induction of
sepsis, endotoxin tolerance of peripheral blood mononuclear cells (PBMCs) and splenocytes was measured at various time points (6 h, 12 h, 24 h, 48 h, 72 h, 5 days, and 7 days), through the measurement of TNF-α production after stimulation with
lipopolysaccharide (LPS) in an ex vivo model. At each time point, we checked for plasma
tumor necrosis factor (TNF)-α,
interleukin (IL)-6, and
IL-10 levels. Moreover, we analyzed
reactive oxygen species (ROS) as measured by
2',7'-dichlorodihydrofluorescein, plasma
lactate, serum
alanine aminotransferase (ALT), and
creatinine levels. Nuclear factor (NF)-κB,
IL-1 receptor-associated kinase (IRAK)-M, and cleaved
caspase 3 levels were measured in the spleen. Endotoxin tolerance, measured by TNF-α production stimulated through LPS in PBMCs and splenocytes, was induced early in the
sepsis model, starting from 6 h after
sepsis. It reached a nadir at 24 to 48 h after
sepsis, and then started to recover. Endotoxin tolerance was more prominent in the
severe sepsis model. Plasma
cytokines peaked at time points ranging from 6 to 12 h after
sepsis. ROS levels peaked at 12 h and then decreased.
Lactate, ALT, and serum
creatinine levels increased up to 24 to 48 h, and then decreased. Phosphorylated p65 and IRAK-M levels of spleen increased up to 12 to 24 h and then decreased. Apoptosis was prominent 48 h after
sepsis, and then recovered. In the rat model of polymicrobial
sepsis, endotoxin tolerance occurred earlier and started to recover from 24 to 48 h after
sepsis.