J Appl Physiol 97: 1349-1357, 2004.
First published May 28, 2004; doi:10.1152/japplphysiol.01161.2003
8750-7587/04 $5.00
Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model
Xizhong Cui,1
Chantal Parent,1
Heather Macarthur,2
Scott D. Ochs,2
Eric Gerstenberg,1
Steve Solomon,1
Yvonne Fitz,1
Robert L. Danner,1
Steven M. Banks,1
Charles Natanson,1
Daniela Salvemini,3 and
Peter Q. Eichacker1
1Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; 2Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, St. Louis 63104; and 3Metaphore Pharmaceuticals, St. Louis, Missouri 63114
Submitted 28 October 2003
; accepted in final form 21 May 2004
Previous analysis showed that selective inhibitors of five different host inflammatory mediators administered for sepsis, although beneficial with severe sepsis and high-control mortality rates, were ineffective or harmful with less severe sepsis. We hypothesized that severity of sepsis would also influence inhibition of superoxide anion, another inflammatory mediator. To test this, 6-h infusions of M40401, a selective SOD mimetic, or placebo were given to antibiotic-treated rats (n = 547) starting 3 h after challenge with differing doses of intravenous Escherichia coli designed to produce low- or high-control mortality rates. There was a positive and significant (P = 0.0008) relationship between the efficacy of M40401 on survival rate and control mortality rates. M40401 increased or decreased the log (odds ratio of survival) (means ± SE), dependent on whether control mortality rates were greater or less than the median (66%) (+0.19 ± 0.12 vs. –0.25 ± 0.10, P = 0.01). In a subset of animals examined (n = 152) at 9 h after E. coli challenge, M40401 increased (mean effect ± SE compared with control) mean arterial blood pressure (8 ± 5 mmHg) and decreased platelets (–37 ± 22 cells x 103/ml) with high-control mortality rates but had opposing effects on each parameter (–3 ± 3 mmHg and 28 ± 19 cells x 103/ml, respectively) with low rates (P 
0.05 for the differing effects of M40401 on each parameter with high- vs. low-control mortality rates). A metaregression analysis of published preclinical sepsis studies testing SOD preparations and SOD mimetics showed that most (16 of 18) had control mortality rates >66%. However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P = 0.03) in a relationship not altered (P = not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P = not significant). Thus, in these preclinical sepsis models, possibly related to divergent effects on vascular function, inhibition of superoxide anion improved survival with more severe sepsis and high-control mortality rates but was less effective or harmful with less severe sepsis. Extrapolated clinically, inhibition of superoxide anion may be most efficacious in septic patients with severe sepsis and a high risk of death.
septic shock; treatments; superoxide dismutase mimetic; M40401
Address for reprint requests and other correspondence: X. Cui, Critical Care Medicine Dept., National Institutes of Health, Bldg. 10, Rm. 7D43, Bethesda, MD 20892 (E-mail: cxizhong{at}mail.cc.nih.gov).
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Copyright © 2004 by the American Physiological Society.
