Decreased tumor necrosis factor production during the initial stages of infection correlates with survival during murine gram-negative sepsis
J. L. Mayoral, C. J. Schweich and D. L. Dunn
Department of Surgery, University of Minnesota, Minneapolis.
Secretion of tumor necrosis factor (TNF)/cachectin occurs during
gram-negative bacterial sepsis in response to macrophage stimulation by
lipopolysaccharide (endotoxin) and may play an early pivotal role in the
subsequent host response. We sought to determine whether administration of:
(1) murine monoclonal antibody directed against endotoxin, (2) steroids, or
(3) antimicrobial agents would abrogate TNF production and whether the
protective capacity would correlate with TNF levels in an experimental
model of murine gram-negative bacterial sepsis. Mice were pretreated with
anti-lipopolysaccharide monoclonal antibody, gentamicin sulfate,
hydrocortisone, or saline and were then challenged with a lethal dose of
intraperitoneal Salmonella minnesota. Murine serum TNF levels were measured
by the L929 fibroblast cytotoxicity assay. Both gentamicin and
anti-lipopolysaccharide monoclonal antibody significantly enhanced
survival, and TNF activity at 1.5 and 3 hours was significantly suppressed
in animals receiving these agents compared with animals that received
either steroids or saline. We conclude that agents such as gentamicin,
which inhibits bacterial replication, or monoclonal antibodies, which may
neutralize lipopolysaccharide, indeed enhance survival, and survival was
correlated with a significant reduction in circulating TNF during the early
stages of infection.
