Alveolar NF-κB signaling regulates endotoxin-induced lung inflammation

The alveolar epithelium participates in host defense through inflammatory pathways that activate NF-κB. Lung infections involving endotoxins trigger acute respiratory distress syndrome (ARDS) in adult and pediatric patients. The purpose of this study was to test the hypothesis that overexpression of NF-κB would worsen and conditional deletion of NF-κB signaling would improve endotoxin-induced lung inflammation using transgenic mouse models.

Two previously described transgenic mouse models were used in which overexpression of the RelA/p65 subunit of NF-κB was targeted to the lung epithelium using an SPC promoter (SPC-RelA) and conditional deletion of the IKKβ molecule involved in NF-κB signaling was targeted to the lung epithelium using Nkx2.1(Cre) (Nkx2.1(Cre);IKKβ(F/F)). Adult transgenic and control mice were injected with intratracheal lipopolysaccharide (LPS) or saline followed by lung harvest at 48 h. Collected tissue included whole lungs from transgenic and control mice which was processed for analysis of BAL, lung histology, chemokine expression, and markers of cell apoptosis as well as collection of freshly isolated AECII cells from wild type mice for additional chemokine and apoptotic marker analysis.

SPC-RelA mice showed significant increases in lung inflammation and injury following LPS injection with increased neutrophil recruitment as compared to wild type and saline treated controls. In contrast, Nkx2.1(Cre); IKKβ(F/F) mice showed markedly decreased lung inflammation and injury with decreased neutrophil recruitment as compared to controls. In both models, lung inflammation was associated with increased cell apoptosis and these findings were confirmed in freshly isolated AECII cells in wild type mice following LPS injection.

Overexpression of NF-κB targeted to the lung epithelium worsened lung inflammation and injury in response to LPS exposure while conditional deletion of NF-κB signaling reduced lung inflammation. Lung inflammation and injury were associated with increased cell apoptosis.