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1Departments of Medicine, 2Comparative Medicine, 3Immunology, 4Microbiology, and 5Pediatrics, University of Washington School of Medicine, Seattle, Washington 98104
Submitted 4 February 2004 ; accepted in final form 21 March 2004
To determine the role of respiratory epithelial cells in the inflammatory response to inhaled endotoxin, we selectively inhibited NF-
B activation in the respiratory epithelium using a mutant IB-
construct that functioned as a dominant negative inhibitor of NF-B translocation (dnIB-). We developed two lines of transgenic mice in which expression of dnIB- was targeted to the distal airway epithelium using the human surfactant apoprotein C promoter. Transgene expression was localized to the epithelium of the terminal bronchioles and alveoli. After inhalation of LPS, nuclear translocation of NF-B was evident in bronchiolar epithelium of nontransgenic but not of transgenic mice. This defect was associated with impaired neutrophilic lung inflammation 4 h after LPS challenge and diminished levels of TNF-, IL-1
, macrophage inflammatory protein-2, and KC in lung homogenates. Expression of TNF- within bronchiolar epithelial cells and of VCAM-1 within peribronchiolar endothelial cells was reduced in transgenic animals. Thus targeted inhibition of NF-B activation in distal airway epithelial cells impaired the inflammatory response to inhaled LPS. These data provide causal evidence that distal airway epithelial cells and the signals they transduce play a physiological role in lung inflammation in vivo.
lipopolysaccharide; cytokines; nuclear factor-B; transgenic mice
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