Regulation of intestinal nuclear factor-kappaB activity and E-selectin expression during sepsis: a role for peroxynitrite.
OBJECTIVE
During sepsis, the production of both nitric oxide and superoxide are increased. Furthermore, NO and O(2)(-) may interact to produce peroxynitrite. The major aim of the present study was to assess the relative roles of NO, O(2)(-), and ONOO- in the regulation of nuclear factor kappaB (NF-kappaB) activity and subsequent E-selectin expression during the early stages of sepsis.


METHODS
Mice were administered 5 microg lipopolysaccharide (LPS) intraperitoneally, and NF-kappaB activity and E-selectin expression in the small intestine were assessed 3 hours later.


RESULTS
In wild-type mice, increased levels of NF-kappaB in nuclear extracts were noted. By contrast, in both inducible nitric oxide synthase-deficient and transgenic Cu/Zn superoxide dismutase-overexpressing mice, NF-kappaB mobilization to the nucleus was diminished. Pretreatment with a ONOO- decomposition catalyst (5,10,15,20-tetrakis[4-sulfonatophenyl]porphyrinato iron [III] [FeTPPS]) resulted in a diminished impact of LPS on NF-kappaB activation. LPS increased vascular E-selectin expression in wild-type mice. E-selectin expression was diminished in inducible nitric oxide synthase-deficient mice after LPS challenge, but E-selectin expression remained elevated in both Cu/Zn superoxide dismutase transgenic mice and wild-type mice pretreated with FeTPPS.


CONCLUSIONS
Our observations suggest that NO, O(2)(-), and ONOO- production are all important mediators in the induction of NF-kappaB activity during endotoxemia and that, in vivo, E-selectin expression on endothelium may not always be associated with whole-organ NF-kappaB activation.
Lush
Cameron W
CW
Department of Physiology, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada N6A 4G5.
Cepinskas
Gediminas
G
Kvietys
Peter R
PR
D000818:Animals; D001424:Bacterial Infections / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014471:Umbilical Veins / Q000378:metabolism
C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D019040:E-Selectin; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D016328:NF-kappa B; D030421:Peroxynitrous Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase