Airway epithelium controls lung inflammation and injury through the NF-kappa B pathway.

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.

• 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.)

Chemical References

• Inflammation Mediators
• Lipopolysaccharides
• NF-kappa B

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)