Abstract |
Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-kappaB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-kappaB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IkappaB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-kappaB activation with consequent production of a variety of proinflammatory cytokines, high- protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-kappaB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IkappaB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-kappaB pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.
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Authors | Dong-sheng Cheng, Wei Han, Sabrina M Chen, Taylor P Sherrill, Melissa Chont, Gye-Young Park, James R Sheller, Vasiliy V Polosukhin, John W Christman, Fiona E Yull, Timothy S Blackwell |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 178
Issue 10
Pg. 6504-13
(May 15 2007)
ISSN: 0022-1767 [Print] United States |
PMID | 17475880
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Inflammation Mediators
- Lipopolysaccharides
- NF-kappa B
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Topics |
- Acute Disease
- Animals
- Cells, Cultured
- Female
- Humans
- Inflammation
(genetics, immunology, metabolism, prevention & control)
- Inflammation Mediators
(metabolism, physiology)
- Lipopolysaccharides
(pharmacology)
- Lung
(immunology, metabolism, pathology)
- Male
- Mice
- Mice, Transgenic
- NF-kappa B
(antagonists & inhibitors, metabolism, physiology)
- Respiratory Mucosa
(immunology, metabolism, pathology)
- Signal Transduction
(genetics, immunology)
- Trachea
(immunology, metabolism, pathology)
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