Spin trap salvage from endotoxemia: the role of cytokine down-regulation.
BACKGROUND
The spin trap alpha-phenyl-N-tert-butyl-nitrone (PBN) affords protection from the lethality of septic (lipopolysaccharide) shock. We hypothesized that PBN may work through down-regulation of the sepsis-induced cytokine cascade.


METHODS
C3H/HEN mice received 30 mg/kg lipopolysaccharide 15 minutes after pretreatment with PBN or vehicle. Animals were monitored for differences in behavior, histopathologic studies, survival, and serum levels of tumor necrosis factor (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) after lipopolysaccharide. Northern blot analyses of TNF, IFN-gamma, c-fos, and IL-6 transcripts were also performed.


RESULTS
Seventy-two-hour survival was significantly higher in the PBN-treated (59/60) compared with the saline-treated animals (13/60; p2 less than 0.005), and the PBN group exhibited a blunted endotoxemic response. TNF levels were significantly lower in the PBN-treated animals at 1 to 6 hours, whereas IFN-gamma levels were depressed at 8 hours. PBN down-regulated TNF transcription at 30 minutes, with maximum lowering of all cytokine transcripts at 6 hours. PBN depressed c-fos transcription within 15 minutes of lipopolysaccharide injection.


CONCLUSIONS
Spin trap protection from endotoxemia may be related to interruption of the cytokine network, with profound effects on transcription and protein elaboration. Such compounds may prove useful in not only sepsis but also other cytokine-free radical-related pathophysiologic alterations.
Pogrebniak
H W
HW
Thoracic Oncology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Merino
M J
MJ
Hahn
S M
SM
Mitchell
J B
JB
Pass
H I
HI
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D015152:Blotting, Northern; D003497:Cyclic N-Oxides; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004731:Endotoxins / Q000097:blood*; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009026:Mortality; D009589:Nitrogen Oxides / Q000378:metabolism / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology; D013113:Spin Labels; D014158:Transcription, Genetic
D001798:Blood Proteins; D003497:Cyclic N-Oxides; D016207:Cytokines; D004731:Endotoxins; D009589:Nitrogen Oxides; D013113:Spin Labels; C029217:phenyl-N-tert-butylnitrone; D012965:Sodium Chloride; D001120:Arginine