Regulation of intestinal nuclear factor-κB activity and E-selectin expression during sepsis: A role for peroxynitrite

Background & Aims: During sepsis, the production of bothnitric oxide and superoxide are increased. Furth ermore, NO and O2 may interact to produce peroxynitrite. The major aim of the present study was to assess the relative roles of NO, O2, and ONOO in the regulation of nuclear factor B (NF-B) activity and subsequent Eselectin expression during the early stages of sepsis. Methods: Mice were administered 5 g lipopolysaccharide (LPS) intraperitoneally, and NF-B activity and Eselectin expression in the small intestine were assessed 3 hours later. Results: In wild-type mice, increased levels of NF-B in nuclear extracts were noted. By contrast, in bothinducible nitric oxide synthase– deficient and transgenic Cu/Zn superoxide dismutase– overexpressing mice, NF-B mobilization to the nucleus was diminished. Pretreatment witha ONOO decomposition catalyst (5,10,15,20-tetrakis[4-sulfonatophenyl]porphyrinato iron [III] [FeTPPS]) resulted in a diminished impact of LPS on NF-B activation. LPS increased vascular Eselectin 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 bothCu/Zn superoxide dismutase transgenic mice and wild-type mice pretreated withFeTPPS. Conclusions: Our observations suggest that NO, O2, and ONOO production are all important mediators in the induction of NF-B activity during endotoxemia and that, in vivo, E-selectin expression on endothelium may not always be associated with wholeorgan NF-B activation.