LPS pretreatment ameliorates multiple organ injuries and improves survival in a murine model of polymicrobial sepsis

The endotoxin tolerance phenotype is characterized with decreased inflammation and increased phagocytosis. We hypothesized that endotoxin tolerance would provide protective effects on experimental sepsis with multiple organ injuries induced by cecal ligation and puncture (CLP). Endotoxin tolerance was induced in male Sprague-Dawley rats with daily intraperitoneal injection of either 0.6 mg/kg of lipopolysaccharide (LPS) or vehicle for four consecutive days before subsequent CLP. Biochemical parameters, histological changes, inflammatory cytokine production, and lung tissue nuclear factor-kappa B (NF-kappa B) activation were assessed post-CLP. In a separate experiment, survival rate was monitored for 7 days after CLP. In vehicle-treated animals, CLP caused multiple organ injuries confirmed by the biochemical variables and histological examination. This was accompanied by an early activation of NF-kappa B in the lung and a substantial increase in plasma levels of tumor necrosis factor-alpha, interleukin-6, and interleukin-10. In contrast, pretreatment with LPS not only alleviated the development of multiple organ injuries after CLP, but also decreased sepsis-induced activation of pulmonary NF-kappa B and reduced plasma cytokines production. In addition, LPS pretreatment improved the survival in rats subjected to CLP. The beneficial effects of endotoxin tolerance indicate the potential of immunomodulatory strategies in the management of severe sepsis.