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1 Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: cxizhong{at}mail.cc.nih.gov.
Although circulatory shock related to lethal toxin (LeTx) may play a primary role in lethality due to Bacillus anthracis infection, its mechanisms are unclear. We investigated whether LeTx-induced shock is associated with inflammatory cytokine and nitric oxide (NO) release. Sprague-Dawley rats with central venous and arterial catheters received 24 h infusions of LeTx (lethal factor 100 ug/kg; protective antigen 200 ug/kg) that produced death beginning at 9 h and a 7 d mortality rate of 53%. By 9 h mean arterial blood pressure, heart rate, pH, and base excess were decreased and lactate and hemoglobin levels were increased in LeTx nonsurvivors compared to LeTx survivors and controls (diluent only) (p
0.05 for each comparing the 3 groups). Despite these changes, arterial oxygen and circulating leukocytes and platelets were not decreased and tumor necrosis factor (TNF) 
, interleukin-1 (IL-1) 
, IL-6, and IL-10 levels were not increased comparing either LeTx nonsurvivors or survivors to controls. Nitrate/nitrite levels and tissue histology also did not differ comparing LeTx animals and controls. In additional experiments, although 24 h infusions of LeTx and E. coli lipopolysaccharide (LPS) produced similar mortality rates (54 and 56% respectively) and times to death (13.2±0.8 vs 11.0±1.7 h respectively), compared to controls only LPS reduced circulating leukocytes, platelets and IL-2 levels and increased TNF , IL-1 and , IL-6, IL-10, interferon 
, granulocyte macrophage-colony stimulating factor, RANTES, migratory inhibitory protein 1,2, and 3 and monocyte chemotactic protein-1 as well as nitrate/nitrite levels (all p 0.05 for the effects of LPS). Thus, in contrast to LPS, excessive inflammatory cytokine and NO release do not appear to contribute to the circulatory shock and lethality occurring with LeTx in this rat model. Although therapies to modulate these host mediators may be applicable for shock caused by LPS or other bacterial toxins, they may not with LeTx.
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