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Airway Epithelium Controls Lung Inflammation and Injury through the NF-κB Pathway

2007; American Association of Immunologists; Volume: 178; Issue: 10 Linguagem: Inglês

10.4049/jimmunol.178.10.6504

1550-6606

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,

Pediatric health and respiratory diseases

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-κB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-κB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IκB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-κB 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-κB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IκB 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-κB 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.