Impaired pulmonary NF-κB activation in response to lipopolysaccharide in NADPH oxidase-deficient mice

Reactive oxygen species (ROS) are thought to be involved in intracellular signaling, including activation of the transcription factor NF-kappaB. We investigated the role of NADPH oxidase in the NF-KB activation pathway by utilizing knockout mice (p47(phox-/-)) lacking the p47(phox) component of NADPH oxidase. Wild-type (WT) controls and P47(phox-/-) mice were treated with intraperitoneal (i.p.) Escherichia coli lipopolysaccharide (LPS) (5 or 20 mug/g of body weight). LPS-induced NF-kappaB binding activity and accumulation of RelA in nuclear protein extracts of lung tissue were markedly increased in WT compared to p47(phox-/-) mice 90 min after treatment with 20 but not 5 mug of i.p. LPS per g. In another model of lung inflammation, RelA nuclear translocation was reduced in p47(phox-/-) mice compared to. WT mice following treatment with aerosolized LPS. In contrast to NF-kappaB activation in p47(phox-/-) mice, LPS-induced production of macrophage inflammatory protein 2 in the lungs and neutrophilic lung inflammation were not diminished in these mice compared to WT mice. We conclude that LPS-induced NF-KB activation is deficient in the lungs of p47(phox-/-) mice compared to WT mice, but this abnormality does not result in overt alteration in the acute inflammatory response.