Neonatal hypersusceptibility to endotoxin correlates with increased tumor necrosis factor production in mice

Septic shock is a major cause of mortality in neonates. The hypothesis was tested that neonatal age is associated with altered sensitivity to shock-inducing bacterial products or proinflammatory cytokines (or both). Mice of different ages were inoculated with various doses of lipopolysaccharide (LPS), superantigenic staphylococcal enterotoxin B (SEB), or recombinant tumor necrosis factor-a (rTNF-a), alone or in combination with the sensitizing agent D-galactosamine. Neonatal mice were markedly more susceptible to LPS-induced lethality but more resistant to SEB than were adults (P .05). Mice of different ages did not differ, however, in their sensitivity to lethal activities of rTNFa. Neonatal susceptibility to LPS and SEB correlated directly with plasma TNF-a but not IFN-g levels, which was confirmed by TNF-a and IFN-g blockade experiments. These data document marked age-related differences in the pathophysiology of septic shock and suggest that IFN-g is not an obligatory mediator of either LPS- or SEB-induced lethality in neonates.