Sublethal hemorrhage blunts the inflammatory cytokine response to endotoxin in a rat model

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 atone mounted an LL-I and TNF response (RNA and protein) much higher than animals subjected to hemorrhage alone, TNF and IL-1 gene expression and protein levels in prehemorchaged animals that received LPS, however, were significantly lower than those of animals that received LPS alone. Conclusion: Hemorrhage induces early IL-l 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.