title: NF-κB-to-AP-1 switch: a mechanism regulating transition from endothelial barrier injury to repair in endotoxemic mice.
abstract: 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-κB-to-AP-1 switch that regulates the transition from barrier injury to repair following endotoxemic MOI. Endothelial NF-κB mediates barrier repair by inhibiting endothelial cell (EC) apoptosis. Blockade of endothelial NF-κB pathway activated the activator protein (AP)-1 pathway (NF-κB-to-AP-1 switch), which compensated for the anti-apoptotic and barrier-repair functions of NF-κB. The NF-κB-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-κB-to-AP-1 switch failed, resulting in enhanced EC apoptosis, augmented endothelial permeability, and impeded transition from barrier injury to recovery. The NF-κB-to-AP-1 switch is a protective mechanism to ensure timely transition from endothelial barrier injury to repair, accelerating barrier restoration following MOI.
authors.affiliation: 1] Centers for Heart and Lung Research and Pulmonary and Critical Care Medicine, the Feinstein Institute for Medical Research, Manhasset, NY 11030, USA [2].
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: 1] Centers for Heart and Lung Research and Pulmonary and Critical Care Medicine, the Feinstein Institute for Medical Research, Manhasset, NY 11030, USA [2].
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Ye
authors.affiliation: Centers for Heart and Lung Research and Pulmonary and Critical Care Medicine, the Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
authors.affiliation: Centers for Heart and Lung Research and Pulmonary and Critical Care Medicine, the Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Shu Fang
authors.initials: SF
authors.lastname: Liu
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000276:immunology*; D019446:Endotoxemia / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009102:Multiple Organ Failure / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D020127:Recovery of Function / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000276:immunology*
chemical_list: D016328:NF-kappa B; D018808:Transcription Factor AP-1