Abstract
Introduction Sepsis is the primary cause of death from infection. We wanted to improve the outcome of sepsis by stimulating innate immunity in combination with modulating the severity of inflammatory responses in rats. Method Sepsis was induced by the injection of feces suspension (control). A 5-day course of G-CSF treatment was given before the septic insult (G-CSF). The inflammatory response was decreased using various doses of the LPS-blocking peptide LBPK95A (5 mg/kg = 100% Combi group, 0.5 mg/kg = 10% Combi group, and 0.05 mg/kg = 1% Combi group). Survival rates were observed. Bacterial clearance, neutrophil infiltration, tissue damage, and the induction of hepatic and systemic inflammatory responses were determined 2 h and 12 h after the septic insult. Results High-dose LBPK95A (100% Combi) reduced the survival rate to 10%, whereas low-dose LBPK95A (10% and 1% Combi) increased the survival rates to 50% and 80%, respectively. The survival rates inversely correlated with multiorgan damage as indicated by the serum levels of ALT and urea. G-CSF treatment increased the white blood cell counts, hepatic neutrophil infiltration, and bacterial clearance in the liver, lung, and blood. The blockade of the LPS-LBP interaction decreased neutrophil infiltration, led to increased white blood cell count, and decreased hepatic neutrophil infiltration, irrespective of dose. However, bacterial clearance improved in the 1% and 10% Combi groups but worsened in the 100% Combi group. G-CSF increased TNF-α and IL-6 levels. Irrespective of dose, the blockade of the LPS-LBP interaction was associated with low systemic cytokine levels and delayed increases in hepatic TNF-α and IL-6 mRNA expression. The delayed increase in cytokines was associated with the phosphorylation of STAT3 and AKT. Conclusion Our results revealed that increasing innate immunity by G-CSF pretreatment and decreasing inflammatory responses using LBPK95A improved the survival rates in a rat sepsis model and could be a novel strategy to treat sepsis.
Highlights
Sepsis is the primary cause of death from infection
Hepatic neutrophil infiltration in the Granulocyte colony-stimulating factor (G-CSF) groups was significantly higher 2 h after septic insult, whereas the application of LBPK95A inhibited neutrophil infiltration in Combi groups
This study was designed to explore whether the dynamic balance between lipopolysaccharide binding protein (LBP)-induced bacterial clearance and LBPmediated LPS-sensitization was decisive for the therapeutic success of G-CSF-induced modulation of innate immunity in sepsis
Summary
Sepsis is defined as the overwhelming reaction to the invasion of microorganisms and their components. Modulation of innate immunity to increase bacterial clearance and decrease the inflammatory response is a novel strategy to treat sepsis. In the intact organism, activated PMNs are key components in host defense during acute bacterial infection [5,6,7], promoting the elimination of bacteria. Binding between LBP and LPS activates the inflammatory response [13] and leads to increased bacterial clearance [14, 15]. One reason for the observed conflicting results of G-CSF-treatment could be an inappropriate balance of the putatively beneficial effect of LBP-mediated bacterial clearance and the detrimental effect of LPSsensitization in the course of sepsis development. We hypothesized that the dynamic balance between LBP-mediated LPS-sensitization and bacterial clearance was decisive for the therapeutic success of G-CSF-induced modulation of innate immunity in sepsis
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