In Project 4, we will test the hypotheses that (i) Nox2-dependent oxidant signaling activates Src kinasedependent ICAM-1-phosphorylation and thereby the recruitment of PMNs in the pulmonary circulation, and that (ii) Src phosphorylation of ICAM-1 in turn protracts Src activation and phosphorylation of caveolin-1 and dynamin-2, thereby triggering caveolae-mediated transcytosis of albumin and endothelial hyper-permeability. These studies will address the following Specific Aims: (1) role of PI3-kinase, PKC zeta, Nox2, and Src signaling, and of Akt phosphorylation of filamin A in the mechanism of ICAM-1 phosphorylation, clustering, and rapid increase in ICAM-1 binding affinity in lung microvascular endothelial cells and PMN uptake in lungs;(2) role of phospho-ICAM-1 in recruitment of SHP2 and protracting Src activation and thereby caveolin-1 and dynamin-2 activation, and thus stimulating caveolae-mediated transcytosis and hyper-permeability of albumin. Project 4 will delineate the signaling mechanisms mediating the post-translafional modification of ICAM-1 in pulmonary microvessel endothelial cells using imaging, cell biology, biochemical, and physiological approaches. We will thereby establish how endothelial cell ICAM-1 shifts to a high-affinity state and promotes PMN adhesion and sequestration and also induces caveolae-mediated hyper-permeability via the transcytosis of albumin. These studies it is hoped will lead to a new understanding of the early PMN-mediated lung inflammatory response and its coupling to lung vascular hyper-permeability. Identification of the key signaling hubs of ICAM-1-mediated endothelial adhesivity and activation of the caveolae-mediated albumin transport pathway is likely to provide novel therapeutic targets directed against infiammatory lung injury.

Public Health Relevance

We will elucidate the role of Src-activated signaling mechanism regulating endothelial adhesivity and thereby permeability of lung microvessels. The proposed studies will for the first time establish the potentially important relationship between Src-activation of ICAM-1, neutrophil adhesion, and activation of the caveolar permeability machinery. Project 4 studies will thus define a novel pathogenic mechanism of ALI/ARDS.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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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
Potje, Simone R; Chen, Zhenlong; Oliveira, Suellen D'Arc S et al. (2017) Nitric oxide donor [Ru(terpy)(bdq)NO]3+ induces uncoupling and phosphorylation of endothelial nitric oxide synthase promoting oxidant production. Free Radic Biol Med 112:587-596
Tsang, Kit Man; Hyun, James S; Cheng, Kwong Tai et al. (2017) Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1?. Stem Cell Reports 9:796-806
Marsboom, Glenn; Chen, Zhenlong; Yuan, Yang et al. (2017) Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension. Mol Biol Cell 28:1177-1185
Andresen Eguiluz, Roberto C; Kaylan, Kerim B; Underhill, Gregory H et al. (2017) Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity. Biomaterials 140:45-57

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