Lung Glycocalyx Mediates Pressure-Induced Permeability

肺糖萼介导压力诱导的渗透性

• 批准号: 7491480
• 负责人: randal Owen dull
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491480
• 关键词: Achievement; Acute; Acute Lung Injury; Agonist; Animals; Attenuated; Biology; Biomechanics; Blood; Blood Vessels; Blood capillaries; Capillary Permeability; Cell surface; Cells; Characteristics; Clinical; Colloids; Cultured Cells; Development; Endothelial Cells; Fluid Balance; Functional disorder; Glycocalyx; Glycoproteins; Glycosaminoglycans; Goals; Heparitin Sulfate; Hyaluronan; In Situ; In Vitro; Individual; Intercellular Junctions; Lead; Liquid substance; Lung; Lung Inflammation; Measures; Mechanics; Mediating; Modeling; Molecular; Morbidity - disease rate; Pathway interactions; Patients; Permeability; Polymers; Property; Rattus; Regulation; Role; Sialoglycoproteins; Signal Transduction; Structure; Structure-Activity Relationship; System; Techniques; Testing; Therapeutic Intervention; capillary; hemodynamics; in vivo; innovation; mortality; novel; novel therapeutics; pressure; response; scaffold; solute; success

DESCRIPTION (provided by applicant): Increased capillary permeability remains a critical determinant of morbidity and mortality among ICU patients. A primary component of the lung permeability barrier is the endothelial glycocalyx, a polymer scaffolding composed of glycoproteins and glycosaminoglycans on the cell surface and overlying the cell-cell junction. We have shown that components of the glycocalyx participate in agonist-mediated signaling, and flow- and pressure-mediated mechano-transduction, all of which result in barrier dysfunction. We hypothesize that the glycocalyx functions as both a molecular filter, which determines fluid and solute flux into the cell-cell junction, and as an active signaling interface between blood born agonists, hemodynamic force and the endothelial cell itself. This application proposes to examine the role of the glycocalyx on barrier function, using intact lungs and a cell-culture model, thus allowing for a direct comparison of the functional attributes of the glycocalyx in vivo vs. in vitro. In Specific Aim 1, we will characterize the role of the glycocalyx on lung capillary permeability in isolated, perfused lungs and in whole animal studies. These studies will examine the glycocalyx as a molecular filter, in agonist-mediated barrier dysfunction and in mechano-transduction. In Specific Aim2, we will characterize the role of specific glycoproteins in mechano-transduction and characterize the mechanistic pathway(s) involved. In Specific Aim 3, we will use sophisticated biophysical techniques to characterize the micro-biomechanical properties of the glycocalyx and its constituents that are fundamental to mechano-transduction. The integrated results of this application will provide a comprehensive understanding of the glycocalyx as an important interface between the capillary wall and the vascular compartment. We believe the results from these studies will provide entirely new information about the regulation of lung capillary barrier properties and could lead to the development of novel therapeutic interventions to attenuate the deleterious effects of increased lung permeability.

描述（由申请人提供）：毛细血管通透性增加仍然是 ICU 患者发病率和死亡率的关键决定因素。肺通透性屏障的主要组成部分是内皮糖萼，这是一种由细胞表面上的糖蛋白和糖胺聚糖组成的聚合物支架，覆盖细胞与细胞的连接处。我们已经证明，糖萼的成分参与激动剂介导的信号传导以及流量和压力介导的机械转导，所有这些都会导致屏障功能障碍。我们假设糖萼既充当分子过滤器（决定进入细胞-细胞连接处的液体和溶质流量），又充当血源激动剂、血流动力学和内皮细胞本身之间的主动信号传导界面。该应用提出使用完整的肺和细胞培养模型来检查糖萼对屏障功能的作用，从而可以直接比较体内和体外糖萼的功能属性。在具体目标 1 中，我们将描述糖萼对离体、灌注肺和整个动物研究中肺毛细血管通透性的作用。这些研究将检查糖萼作为分子过滤器、激动剂介导的屏障功能障碍和机械传导。在 Specific Aim2 中，我们将描述特定糖蛋白在机械转导中的作用，并描述所涉及的机制途径。在具体目标 3 中，我们将使用复杂的生物物理技术来表征糖萼及其成分的微生物力学特性，这些特性对于机械传导至关重要。该应用的综合结果将提供对糖萼作为毛细血管壁和血管室之间的重要界面的全面理解。我们相信，这些研究的结果将提供有关肺毛细血管屏障特性调节的全新信息，并可能导致开发新的治疗干预措施，以减轻肺通透性增加的有害影响。