Compromise of the pulmonary endothelial cell (EC) barrier is induced by mechanical stress which isassociated with ventilator-induced lung injury (VILI), This process leads to increased vascular permeability,alveolar flooding, leukocyte infiltration, hypoxemia, and increased morbidity and mortality. Project #3scientists have previously identified cytoskeletal mechanisms of EC barrier regulation by barrier-protectivestrategies (oxidized phosphocholine, sphingosine 1-phosphate, physiologic shear stress and cyclic stretch(CS) and barrier-disruptive mechanical and chemical stimuli (thrombin, pathologic CS). In addition, thesePPG investigator have described the critical involvement of small GTPases Rac and Rho in remodeling ofEC cytoskeleton and cell contacts essential for EC barrier regulation. Our published results and preliminarydata strongly suggest that magnitude-dependent modulation of Rac and Rho activities by CS significantlyimpacts agonist-induced EC permeability changes. The Project #3 hypothesis is that pathologic CS andvascular endothelial growth factor (VEGF), known to be elevated during VILI, promote lung endothelialbarrier dysfunction via synergistic effects on Rho pathway-mediated EC permeability. These processes arecounterbalanced by Rac-dependent mechanisms induced by barrier-protective stimuli such as hepatocytegrowth factor (HGF) and physiologic stretch. We speculate that focal adhesions may act as mechanosensorsand modulate small GTPase activities via specific paxillin interactions with Rac and Rho protein regulators.
Specific Aim #1 will study synergistic effects between pathologic CS and VEGF on activation of RhomediatedEC barrier dysfunction.
Specific Aim #2 will define barrier-protective strategies in amelioration ofVILI-associated EC barrier dysfunction via changes in a balance between the Rho and Rac activities.
Specific Aim #3 will study novel mechanisms of Rac/Rho regulation by mechanochemical factors viainteractions between wild type paxillin (or/and paxillin containing the Gly73Ser polymorphism) interactionswith modulators of Rac and Rho activity (GIT2, betaPIX, PAK1 and p190RhoGAP). These studies willuncover novel molecular mechanisms involved in the pathogenesis and resolution of ventilator-induced lunginjury.
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