Respiratory epithelial cells regulate lung inflammation in response to inhaled endotoxin.
To determine the role of respiratory epithelial cells in the inflammatory response to inhaled endotoxin, we selectively inhibited NF-kappa B activation in the respiratory epithelium using a mutant I kappa B-alpha construct that functioned as a dominant negative inhibitor of NF-kappa B translocation (dnI kappa B-alpha). We developed two lines of transgenic mice in which expression of dnI kappa B-alpha 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-kappa 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-alpha, IL-1 beta, macrophage inflammatory protein-2, and KC in lung homogenates. Expression of TNF-alpha within bronchiolar epithelial cells and of VCAM-1 within peribronchiolar endothelial cells was reduced in transgenic animals. Thus targeted inhibition of NF-kappa 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.
Skerrett
Shawn J
SJ
Department of Medicine, University of Washington School of Medicine, Seattle, 98104, USA. shawn@u.washington.edu
Liggitt
H Denny
HD
Hajjar
Adeline M
AM
Ernst
Robert K
RK
Miller
Samuel I
SI
Wilson
Christopher B
CB
D000280:Administration, Inhalation; D000818:Animals; D001980:Bronchi / Q000378:metabolism; D001991:Bronchitis / Q000517:prevention & control; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D016209:Interleukin-8 / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced* / Q000517:prevention & control; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology / Q000502:physiology*
D016207:Cytokines; D020672:I-kappa B Proteins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D037721:Pulmonary Surfactant-Associated Protein C; D000072000:NF-KappaB Inhibitor alpha; D009195:Peroxidase