Endothelial barrier disruption is a hallmark of multiple organ injury (MOI). However, mechanisms governing the restoration of endothelial barrier function are poorly understood. Here, we uncovered an NF-kappa B-to-AP-1 switch that regulates the transition from barrier injury to repair following endotoxemic MOI. Endothelial NF-kappa B mediates barrier repair by inhibiting endothelial cell (EC) apoptosis. Blockade of endothelial NF-kappa B pathway activated the activator protein (AP)-1 pathway (NF-kappa B-to-AP-1 switch), which compensated for the anti-apoptotic and barrier-repair functions of NF-kappa B. The NF-kappa B-to-AP-1 switch occurred at 24 hours (injury to repair transition phase), but not at 48 hours (repair phase) post-LPS, and required an inflammatory signal within the endothelium. In the absence of an inflammatory signal, the NF-kappa B-to-AP-1 switch failed, resulting in enhanced EC apoptosis, augmented endothelial permeability, and impeded transition from barrier injury to recovery. The NF-kappa B-to-AP-1 switch is a protective mechanism to ensure timely transition from endothelial barrier injury to repair, accelerating barrier restoration following MOI.
Faculty; Northwell Researcher
School of Medicine; Northwell Health
General Internal Medicine
Molecular Medicine; Surgery; Pulmonary, Critical Care, and Sleep Medicine