Airway epithelium controls lung inflammation and injury through the NF-κB pathway

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 investi gated whether NF-kappa B pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-kappa B activation or inhibition in vivo. In transgenic mice that express a constitutively active form of I kappa B kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-kappa B 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-kappa B in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of I kappa B 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-kappa B 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. The Journal of Immunology, 2007,178: 6504-6513.