Control of lung permeability by oxidized phospholipids

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DESCRIPTION (provided by applicant): Oxidized phospholipids appear among other bioactive substances in lung circulation under pathological conditions such as acute lung injury, sepsis, lung inflammation, and ventilator-induced lung injury. Lung vascular barrier function under these conditions is largely compromised, but severity of EC dysfunction is determined by a balance between barrier-disruptive and barrier-protective agents present in pulmonary circulation. Oxidation of a natural phospholipid component, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) reproduces a wide spectrum of physiological effects exerted by oxidized phospholipids. Although precise role of OxPAPC in barrier protection has not been yet evaluated, our preliminary studies strongly suggest barrier protective effects of OxPAPC on human pulmonary EC and link them to the actin cytoskeletal remodeling, enhanced intercellular interaction via adherens junctions (AJ), and peripheral remodeling of focal adhesions (FA). We hypothesize that bioactive components of OxPAPC may contribute to the vascular barrier integrity in the injured lung by triggering intracellular signaling pathways mediated by small GTPases Rac and Cdc42 and their downstream cytoskeletal, FA and AJ protein targets. Specific Aim #1 will determine specific components of oxidized phospholipids involved in the lung barrier protection using cell culture and animal models, and explore Rac/Cdc42-dependent regulation of EC cytoskeletal organization and barrier protection. Specific Aim #2 will determine FA protein targets involved in Rac/Cdc42-mediated FA remodeling related to EC barrier promotion. Specific Aim #3: will study involvement of Rac- and Cdc42-dependent mechanisms in the OxPAPC-mediated AJ enhancement and investigate an interaction of FA and AJ protein complexes in OxPAPC-mediated barrier protection. We believe that the results obtained in this study will significantly impact our understanding of the role of oxidized phospholipids in the EC barrier regulation mediated via Rac and Cdc42-specific mechanisms (SA#1) involving remodeling of focal adhesions (SA#2) and adherens junctions (SA#3), and allow us to develop new insights into the role of oxidized phospholipids in the compensatory mechanisms of the lung barrier protection under life-threatening conditions, such as acute lung injury and inflammation.