Endothelial barrier dysfunction is a central factor in the pathogenesis of Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI). In recent years, considerable advances have been made in the understanding of how intracellular signaling pathways modulate the disruption and assembly of adherens junctions (AJs). Re-annealing of AJs is a metabolically active process. Yet, little is known about the role of endothelial metabolism as a modulator of endothelial barrier function and restoration of lung vascular injury. Our Supporting Data demonstrate that endothelial cells respond to inflammatory activation with upregulation of signaling via the hypoxia-inducible factor HIF1?, and its crucial downstream metabolic target PFK-FB3, a critical regulatory enzyme for glycolysis. This glycolytic shift is accompanied by concomitant upregulation of mitochondrial glutamine metabolism, which compensates for the loss of mitochondrial glucose oxidation and enables cells to use glutamine as an alternate mitochondrial TCA cycle fuel. We observed that inhibition of PFK- FB3 prevents restoration of endothelial barrier function following lung injury, thus underscoring the adaptive role of PFK-FB3 and increased glycolysis during endothelial barrier restoration. Based on these findings, we posit that induction of glycolysis in lung microvessel endothelial cells serves as a homeostatic mechanism mediating the restoration of endothelial barrier function and lung fluid balance. In Project 2, we will pursue the following Specific Aims: (1a) We will define the mechanisms of PFK-FB3-mediated activation of glycolysis and compensatory glutaminolysis in lung endothelial cells as induced by inflammation and endothelial injury, and determine the requisite role of these metabolic shifts in repairing endothelial barrier; (1b) we will determine the spatial-temporal role of PFK-FB3-mediated activation of glycolysis in the re-annealing of AJs and restoring endothelial barrier integrity, and (2) We will determine the role of endothelial metabolic reprogramming via PFK-FB3 in restoring lung endothelial barrier integrity and fluid balance following inflammatory lung injury in models of ALI. Using state-of-the-art metabolic analyses, engineered protein constructs and biosensors as well as novel genetic mouse models, we will define the metabolic mechanisms activated by inflammatory injury of the lung endothelium and their role in restoring the lung endothelial barrier. Our long-term goal is to identify metabolic targets and switches that will promote and accelerate the recovery of the endothelial barrier and normalize lung fluid balance to mitigate acute lung injury.

Public Health Relevance

Endothelial barrier dysfunction is a central factor in the pathogenesis of acute respiratory distress syndrome (ARDS). We will study how cellular metabolism regulates the restoration of the lung endothelial junctional barrier and fluid balance after inflammatory injury. This research will help identify new metabolism-based therapies to prevent and treat acute lung injury during severe infections.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1)
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Xiao, Lei
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University of Illinois at Chicago
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Marsboom, Glenn; Rehman, Jalees (2018) Hypoxia Signaling in Vascular Homeostasis. Physiology (Bethesda) 33:328-337
Lv, Yang; Kim, Kyungho; Sheng, Yue et al. (2018) YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circ Res 123:43-56
Christoforidis, Theodore; Driver, Tom G; Rehman, Jalees et al. (2018) Generation of controllable gaseous H2S concentrations using microfluidics. RSC Adv 8:4078-4083
Di, Anke; Xiong, Shiqin; Ye, Zhiming et al. (2018) The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation. Immunity 49:56-65.e4
Chen, Zhenlong; D S Oliveira, Suellen; Zimnicka, Adriana M et al. (2018) Reciprocal regulation of eNOS and caveolin-1 functions in endothelial cells. Mol Biol Cell 29:1190-1202
Le Master, Elizabeth; Huang, Ru-Ting; Zhang, Chongxu et al. (2018) Proatherogenic Flow Increases Endothelial Stiffness via Enhanced CD36-Mediated Uptake of Oxidized Low-Density Lipoproteins. Arterioscler Thromb Vasc Biol 38:64-75
Komarova, Yulia; Kruse, Kevin J; Mehta, Dolly et al. (2017) Response by Komarova et al to Letter Regarding Article, ""Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability"". Circ Res 120:e28
Mittal, Manish; Nepal, Saroj; Tsukasaki, Yoshikazu et al. (2017) Response by Mittal et al to Letter Regarding Article, ""Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury"". Circ Res 121:e87
Soni, Dheeraj; Regmi, Sushil C; Wang, Dong-Mei et al. (2017) Pyk2 phosphorylation of VE-PTP downstream of STIM1-induced Ca2+ entry regulates disassembly of adherens junctions. Am J Physiol Lung Cell Mol Physiol 312:L1003-L1017
Oliveira, Suellen D S; Castellon, Maricela; Chen, Jiwang et al. (2017) Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-?-driven pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 312:L760-L771

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