Alveolar epithelial NF-κB/RelA guards the lung against bacterial infection.

Acute respiratory distress syndrome (ARDS), an acute inflammatory lung injury (ALI), is a common and highly fatal lung disease without effective therapy and is primarily caused by infections. Despite lack of genetic evidence, the transcription factor NF-κB has long been a target of great interest for ALI/ARDS treatment, given its high activation by infections and its potent ability in cytokine induction. Here, using lung epithelial cell-specific knockout mice, we report that RelA, the prototypical member of NF-κB, is required for the protection of alveolar epithelial cells from death caused by bacterial infection, thereby vital for lung injury prevention. Compared to wild type controls, mice with RelA deletion selectively in alveolar epithelial type 2 (AT2) cells had significantly higher mortality in response to the lung infection by Pseudomonas aeruginosa. The worse mortality was associated with increased lung injury, alveolar epithelial barrier permeability, and protein leakage into the alveoli. Somewhat more unexpected, bacterial loads, total immune cells as well as the individual numbers of macrophages, neutrophils and lymphocytes in the alveolar lavage were comparable between WT and RelA KO mice. Mechanistically, AT2 cell-intrinsic RelA was indispensable for inducing the pro-survival genes Bcl2 and Bcl-xL to maintain cell survival and integrity after infection. These data reveal a previously unexplored role of NF-κB in preventing ALI/ARDS and provide a mechanistic basis for designing NF-κB-targeted therapies for this most lethal disease.