Regulation of intestinal nuclear factor-kappaB activity and E-selectin expression during sepsis: a role for peroxynitrite.

Abstract

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. 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. 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. 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.