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B Activation in Lipopolysaccharide-Induced Airway Inflammation1

Vermont Lung Center and Departments of
*
Medicine and
Pathology, University of Vermont, Burlington, VT 05405
To reveal the causal role of airway epithelial NF-
B activation in evoking airway inflammation, a transgenic mouse was created expressing a mutant version of the inhibitory protein I-
B
. This I-
B
superrepressor (I-
B
SR) acts to repress NF-
B activation exclusively in airway epithelial cells, under the transcriptional control of the rat CC10 promoter (CC10-I-
B
SR). Compared with transgene-negative littermates, intranasal instillation of LPS did not induce nuclear translocation of NF-
B in airway epithelium of CC10-I-
B
SR transgenic mice. Consequently, the influx of neutrophils into the airways and secretion of the NF-
B-regulated neutrophilic chemokine, macrophage-inflammatory protein-2, and the inflammatory cytokine, TNF-
, were markedly reduced in CC10-I-
B
SR mice relative to the transgene-negative mice exposed to LPS. Despite an inability to activate NF-
B in airway epithelium, resident alveolar macrophages from transgene-positive mice were capable of activating NF-
B in a manner indistinguishable from transgene-negative mice. These findings demonstrate that airway epithelial cells play a prominent role in orchestrating the airway inflammatory response to LPS and suggest that NF-
B signaling in these cells is important for modulating innate immune responses to microbial products.
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