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Sublethal hemorrhage blunts the inflammatory cytokine response to endotoxin in a rat model
E E Zervos1, A A Kramer, K F Salhab
1Department of Surgery, University of South Florida College of Medicine, Tampa, USA.
Background:
Tolerance to lipopolysaccharide (LPS) induced by previous hemorrhage in mice is associated with a blunted interleukin 1 (IL-1) response, suggesting down-regulation of the cytokine cascade as a possible protective mechanism. This study was undertaken to determine whether prehemorrhage induces attenuation of the cytokine response to sepsis beyond IL-1 in a rat model and whether this response occurs at the level of gene transcription.
Methods:
Sprague-Dawley rats underwent sublethal hemorrhage, lethal intraperitoneal endotoxin, or sublethal hemorrhage with delayed lethal endotoxin. Animals were killed 12 hours after LPS injection or 24 hours after hemorrhage. IL-1 and tumor necrosis factor (TNF) mRNA levels were determined on total splenic RNA using reverse-transcriptase polymerase chain reaction, and serum cytokine levels were determined using enzyme-linked immunosorbent assay.
Results:
Animals that received LPS alone mounted an IL-1 and TNF response (RNA and protein) much higher than animals subjected to hemorrhage alone. TNF and IL-1 gene expression and protein levels in prehemorrhaged animals that received LPS, however, were significantly lower than those of animals that received LPS alone.
Conclusion:
Hemorrhage induces early IL-1 and TNF gene expression, which blunts their subsequent expected increase after endotoxic challenge. These findings validate previously documented immune-modulated protective effects of the first insult in a two-hit model.