HEMORRHAGE ACTIVATES NF-KAPPA-B IN MURINE LUNG MONONUCLEAR-CELLS IN-VIVO

Hemorrhage rapidly increases the expression of proinflammatory and imm unoregulatory cytokines in the lungs. Binding elements for the nuclear transcriptional regulatory factors (NF)-kappa B and NF-IL6 (C/EBP bet a) are present in the promoter regions of multiple cytokine genes, inc luding those whose expression is increased after blood loss. In the pr esent experiments, we found increased activation in vivo of NF-kappa B in lung mononuclear cells, but not in splenocytes, taken from mice 1 h after hemorrhage. In contrast, hemorrhage did not activate NF-IL6 in lung cells or splenocytes. Inhibition of xanthine oxidase by prior fe eding of a tungsten-enriched diet prevented hemorrhage-induced activat ion in lung cells of NF-kappa B. Incubating splenocytes in vitro with xanthine oxidase activated NF-kappa B but not NF-IL6. Xanthine oxidase -induced activation of NF-kappa B was inhibited by manganese superoxid e dismutase, but not by catalase. These results suggest that xanthine oxidase-mediated superoxide anion-dependent activation of NF-kappa B o ccurs in vivo and in vitro. This mechanism may contribute to increased lung cytokine responses after hemorrhage.