Transcellular Mechanisms of Endothelial Permeability and Pulmonary Edema

内皮通透性和肺水肿的跨细胞机制

• 批准号: 7367820
• 负责人: Asrar B. Malik
• 金额: $ 33.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367820
• 关键词: Accounting; Address; Adherens Junction; Adult Respiratory Distress Syndrome; Albumins; Anti-Idiotypic Antibodies; Antibodies; Apical; Arts; Binding Proteins; Blood Vessels; Blood capillaries; CAV1 gene; Caveolae; Caveolins; Cell membrane; Cells; Clathrin; Complex; Condition; Coupled; Data; Disease; Disruption; Electron Microscopy; Elements; Endothelial Cells; Endothelium; Event; Exocytosis; Figs - dietary; Financial compensation; Fluid Balance; Gangliosides; Gold; Homeostasis; Inflammatory; Knockout Mice; Lipopolysaccharides; Liquid substance; Lung; Maintenance; Mediating; Membrane; Microvascular Permeability; Modeling; Molecular; Mus; Nature; Nitric Oxide; Numbers; Pathogenesis; Pathway interactions; Permeability; Phosphorylation; Plasma Proteins; Play; Population; Principal Investigator; Process; Production; Protein Biosynthesis; Proteins; Pulmonary Circulation; Pulmonary Edema; Pulmonary artery structure; Pulmonary vessels; Rattus; Regulation; Relative (related person); Respiratory Diaphragm; Role; Secondary to; Sepsis; Small Interfering RNA; Structural Protein; Structure; Structure of parenchyma of lung; Surface; Testing; Tissues; Tracer; Transcriptional Activation; Up-Regulation; Vascular Endothelial Cell; Vesicle; Wild Type Mouse; Work; base; capillary; caveolin 1; cellubrevin; coated pit; density; human NOS3 protein; in vivo; knock-down; macromolecule; neutralizing monoclonal antibodies; novel strategies; prevent; programs; pulmonary vascular permeability; receptor; regional difference; solute; transcription factor; transcytosis; vascular bed; venule; vesicular SNARE proteins

The transvascular exchange of fluid and solutes is an essential function of the pulmonary circulation required for the maintenance of lung tissue homeostasis. Increased lung endothelial permeability plays an important role in the pathogenesis of lung inflammatory states such as ARDS. A fundamental, but poorly understood, mechanism of endothelial transport involves the formation of vesicle carriers that transport plasma proteins, such as albumin. The overall objective of Project 1 is to define the nature of the transcellular pathway, its regulation, and its role in the mechanism of increased lung endothelial permeability. The proposed studies have the following specific aims: (i) Specific Aim #1: to determine (i) the segmental differences in the interactions of albumin with pulmonary vascular endothelial cells in vivo via the Albumin Binding Proteins (ABPs) and (ii) transcellular albumin transport in these segments; Specific Aim #2: to (i) determine the role of caveolin-1 in regulating pulmonary vascular endothelial barrier function (using CAV 1-/ mice and the siRNA strategy to suppress caveolin-1 expression in lung vascular endothelial cells) and (ii) establish the role of a described population of caveolin-1-independent vesicles in lung vascular endothelial transport; Specific Aim #3: to address the role of caveolin-1 in regulating pulmonary microvascular permeability via inter-endothelial junctions; and Specific Aim #4: to address the mechanisms of upregulation of caveolin- 1 induced by lipopolysaccharide and its consequences in increasing pulmonary vascular permeability via trannscytosis. Project 1 addresses the mechanisms by which albumin is transported through pulmonary vascular endothelial cells by a transcellular mechanism involving transcytosis under both normal conditions and after sepsis. Thus, Project 1 addresses the mechanisms by which albumin is transported through pulmonary vascular endothelial cells by a transcellular mechanism involving transcytosis under both normal conditions and after sepsis. Since the loss of pulmonary vascular endothelial barrier function is a key factor in the pathogenesis of lung inflammatory disease, such as ARDS, these studies will be important in defining the role of permeability pathways that contribute to protein-rich pulmonary edema. With an advanced understanding of these pathways, it will possible to specifically target these pathways and prevent the endothelial barrier disruption.

流体和溶质的跨血管交换是维持肺组织内稳态所必需的肺循环的基本功能。肺内皮细胞通透性增加在ARDS等肺炎性状态的发病机制中起重要作用。内皮运输的一种基本但知之甚少的机制涉及形成运输血浆蛋白(如白蛋白)的囊泡载体。项目1的总体目标是确定跨细胞途径的性质，它的调节，以及它在肺内皮细胞通透性增加的机制中的作用。拟议的研究有以下特定目标：(I)特定目标#1：确定(I)白蛋白通过白蛋白结合蛋白(ABPs)与活体肺血管内皮细胞相互作用的节段性差异以及(Ii)白蛋白在这些节段中的跨细胞转运；特定目标#2：确定小窝蛋白-1在调节肺血管内皮细胞屏障中的作用 功能(使用CAV1-/小鼠和siRNA策略抑制肺血管内皮细胞中小窝蛋白-1的表达)和(Ii)确定所描述的一组小窝蛋白-1非依赖性小泡在肺血管内皮细胞运输中的作用；具体目的#3：研究小窝蛋白-1通过内皮间连接调节肺微血管通透性的作用；以及具体目的#4：研究小窝蛋白-1上调的机制 脂多糖诱导的小窝蛋白-1及其通过转胞增加肺血管通透性的后果。项目1阐述了白蛋白在正常情况下和败血症后通过涉及细胞转运的跨细胞机制通过肺血管内皮细胞运输的机制。因此，项目1解决了白蛋白通过肺血管内皮细胞运输的机制 在正常情况下和脓毒症后，通过一种涉及跨细胞作用的跨细胞机制来激活细胞。由于肺血管内皮细胞屏障功能的丧失是肺部炎症性疾病(如ARDS)发病机制中的一个关键因素，这些研究将对确定通透性通路在富含蛋白质的肺水肿中的作用具有重要意义。随着对这些途径的深入了解，将有可能专门针对这些途径 并防止内皮细胞屏障的破坏。