Targeted immunomodulation of the NF-κB pathway in airway epithelium impacts host defense against Pseudomonas aeruginosa

We investigated the impact of inflammatory signaling in airway epithelial cells on host defense against Pseudomonas aeruginosa, a major cause of nosocomial pneumonia. In mice, airway instillation of P. aeruginosa resulted in NF-kappa B activation in the lungs that was primarfly localized to the bronchial epithelium at 4 h, but was present in a variety of cell types by 24 h. We modulated NF-kappa B activity in airway epithelium by intratracheal delivery of adenoviral vectors expressing RelA (AdRelA) or a dominant inhibitor of NF-kappa B before P. aeruginosa infection. Bacterial clearance was enhanced by up-regulation of NF-kappa B activity following AdRelA administration and was impaired by treatment with a dominant inhibitor of NF-kappa B. The TNF-alpha concentration in lung lavage was increased by AdRelA treatment and beneficial effects of NF-kappa B up-regulation were abrogated in TNF-alpha-deficient mice. In contrast, NF-kappa B inhibition reduced MIP-2 expression and neutrophil influx following P. aeruginosa infection. Therefore, inflammatory signaling through the NF-kappa B pathway in airway epithelial cells critically regulates the innate immune response to P. aeruginosa.