The acute-phase response protects mice from D-galactosamine sensitization to endotoxin and tumor necrosis factor-alpha.
D-Galactosamine is an hepatocyte-specific inhibitor of RNA synthesis. It has been used to sensitize animals both to the lethal effects of bacterial endotoxin (lipopolysaccharide) and to a principal lipopolysaccharide-induced mediator of shock, tumor necrosis factor-alpha. The mechanism by which this sensitization occurs is unknown. Because lipopolysaccharide, acting through a network of cytokines, provokes the transcription of a number of hepatic acute-phase proteins, we postulated that the lipopolysaccharide-sensitizing effect of D-galactosamine could be caused by its inhibition of acute-phase product transcription. We confirmed that the acute-phase response to lipopolysaccharide was attenuated by simultaneous administration of D-galactosamine. However, when the acute-phase response was induced by subcutaneous turpentine 24 hr before D-galactosamine administration, the effect of D-galactosamine on circulating acute-phase reactants was negligible. Furthermore, induction of an a priori acute-phase response protected mice from both D-galactosamine/lipopolysaccharide and D-galactosamine/tumor necrosis factor-alpha-induced death. The turpentine-induced acute-phase response did not decrease endogenous tumor necrosis factor-alpha production after lipopolysaccharide, nor did it affect the clearance of larger doses of injected tumor necrosis factor-alpha. Thus we suggest that the acute-phase response protects against death in D-galactosamine-sensitized mice through an interaction with mediators of shock subsequent to tumor necrosis factor-alpha release.
Alcorn
J M
JM
Department of Medicine, Veterans Affairs Medical Center, San Diego, California.
Fierer
J
J
Chojkier
M
M
D000042:Absorption; D000210:Acute-Phase Reaction / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D004357:Drug Synergism; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D005688:Galactosamine / Q000494:pharmacology*; D008107:Liver Diseases / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014425:Turpentine
D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D014425:Turpentine