Sublethal doses of Bacillus anthracis lethal toxin inhibit inflammation with lipopolysaccharide and Escherichia coli challenge but have opposite effects on survival.
BACKGROUND
On the basis of the findings of previous in vitro studies, we hypothesized that anthrax lethal toxin (LeTx) would have anti-inflammatory effects in vivo.


METHODS
We investigated the effects of sublethal doses of LeTx in rats receiving intravascular challenge with lipopolysaccharide (LPS) or intratracheal challenge with Escherichia coli.


RESULTS
In rats receiving 24-h infusions of LPS, compared with control rats, pretreatment with high or low sublethal doses of LeTx 3 h before infusion produced similar patterns of reduction in the hazards ratio (HR) of survival at 168 h (0.60 [95% confidence interval {CI}, 0.37-0.98]; P=.03, for the doses combined). LeTx increased mean arterial blood pressure throughout the period of LPS infusion (P=.001); decreased the levels of 10 of 13 cytokines assessed (i.e., interleukin [IL]-1 alpha , IL-1 beta , IL-2, IL-4, IL-6, IL-10, interferon- gamma , tumor necrosis factor- alpha , granulocyte macrophage-colony-stimulating factor, migratory inhibitory protein [MIP]-1 alpha , MIP-2, MIP-3 alpha , and RANTES) at 2 h; decreased all 13 cytokine levels at 8 h; decreased only 4 cytokine levels at 24 h; and decreased the plasma level of nitric oxide (NO) at 8 h and 24 h but not at 2 h (P< or =.02, for the effect of LeTx, across time, on both cytokine levels and the NO level). Although pretreatment with LeTx before challenge with E. coli altered mean arterial blood pressure, cytokine levels, and the NO level in a pattern similar to that noted in association with LPS infusion, it increased the HR in a pattern different from that associated with LPS (4.36 [95% CI, 0.3-63.4]; P=.04, for the effects of LeTx with LPS vs. E. coli).


CONCLUSIONS
Inhibition of inflammation with LeTx can occur in vivo, and, although beneficial with noninfectious stimuli, it may be harmful with bacteria.
Critical Care Medicine Department, Clinical Center, Bethesda, Maryland 20892, USA.
Xizhong
X
Cui
Yan
Y
Li
Xuemei
X
Li
Michael
M
Haley
Mahtab
M
Moayeri
Yvonne
Y
Fitz
Stephen H
SH
Leppla
Peter Q
PQ
Eichacker
D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage*; D001408:Bacillus anthracis / Q000737:chemistry*; D001427:Bacterial Toxins / Q000008:administration & dosage*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004347:Drug Interactions; D004926:Escherichia coli / Q000378:metabolism / Q000472:pathogenicity*; D007249:Inflammation / Q000139:chemically induced / Q000382:microbiology / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000633:toxicity*; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D051381:Rats
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D016207:Cytokines; D008070:Lipopolysaccharides; C030325:anthrax toxin; D009569:Nitric Oxide