Control of lung permeability by oxidized phospholipids

描述（由申请方提供）：在病理条件下，如急性肺损伤、脓毒症、肺部炎症和呼吸机诱导的肺损伤，氧化磷脂与其他生物活性物质一起出现在肺循环中。在这些条件下，肺血管屏障功能在很大程度上受到损害，但EC功能障碍的严重程度取决于肺循环中存在的屏障破坏剂和屏障保护剂之间的平衡。天然磷脂组分1-棕榈酰-2-花生四烯酸酰-sn-甘油基-3-磷酸胆碱（OxPAPC）的氧化再现了氧化磷脂产生的广泛生理效应。虽然尚未评估OxPAPC在屏障保护中的确切作用，但我们的初步研究强烈表明OxPAPC对人肺EC的屏障保护作用，并将其与肌动蛋白细胞骨架重塑、通过粘附连接（AJ）增强的细胞间相互作用以及局部粘附（FA）的外周重塑联系起来。我们推测OxPAPC的生物活性成分可能通过触发由小GTP酶Rac和Cdc 42及其下游细胞骨架、FA和AJ蛋白靶点介导的细胞内信号传导途径，促进损伤肺的血管屏障完整性。 具体目标#1将使用细胞培养和动物模型确定参与肺屏障保护的氧化磷脂的特定成分，并探索EC细胞骨架组织和屏障保护的Rac/Cdc 42依赖性调节。具体目标#2将确定参与与EC屏障促进相关的Rac/Cdc 42介导的FA重塑的FA蛋白靶标。具体目标#3：将研究参与的Rac和Cdc 42依赖机制在OxPAPC介导的AJ增强和调查的相互作用FA和AJ蛋白复合物在OxPAPC介导的屏障保护。我们认为，本研究中获得的结果将显著影响我们对氧化磷脂在EC屏障调节中的作用的理解，所述EC屏障调节通过Rac和Cdc 42特异性机制（SA#1）介导，涉及局部粘连（SA#2）和粘连连接（SA#3）的重塑，并使我们对氧化磷脂在危及生命的条件下肺屏障保护的补偿机制中的作用有了新的认识，例如急性肺损伤和炎症。

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.