SPATIAL DISTRIBUTION OF LUNG PROTEIN LEAK IN ENDOTOXEMIA

内毒素血症肺蛋白渗漏的空间分布

• 批准号: 6388747
• 负责人: ANTHONY J GERBINO
• 金额: $ 1.03万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6388747
• 关键词: adult respiratory distress syndrome; albumins; histopathology; microcirculation; protein localization; pulmonary edema; respiratory circulation; septic shock; swine; vascular endothelium permeability

ARDS is patchy even when the initial insult to the lung is diffuse, but the spatial distribution of injury and potential mediators have not been fully explored. Increased vascular permeability is central to the pathogenesis of ARDS, and regional differences may contribute to heterogeneous lung injury. Our first hypothesis is that rates of protein leak vary throughout the lung during endotoxemia and have a non-random spatial distribution. We will measure rates of albumin leak into the extravascular space in 1.0 cm3 lung regions in endotoxemic pigs to characterize their spatial distribution, and validate leak rates as measures of local histologic injury. The observed spatial distribution of leak rates will suggest mediators of protein leak that share a similar spatial distribution. Our second hypothesis is that differences in regional pulmonary blood flow (Q) cause local differences in vascular permeability and protein leak. We will make high resolution measurements of Q, albumin leak rate, and plasma volume (a surrogate for capillary surface area [CSA]) to assess the correlation between regional Q and albumin leak rates, and determine whether this correlation is explained by effects of Q on vascular permeability or capillary surface area. Our third hypothesis is that variability in regional Q is increased during endotoxemia, and redistribution of regional Q contributes to ventilation/perfusion (V/Q) inequality rather than resulting from hypoxic pulmonary vasoconstriction. We will make high resolution measurements of regional V and Q before and during endotoxemia and quantify changes in their variability, spatial distribution, and V/Q matching. Characterizing regional differences in protein leak is an important first step in understanding the heterogeneity of lung injury and potential mediators of non-cardiogenic pulmonary edema. If high regional blood flows or associated microvascular pressures increase vascular permeability during endotoxemia, strategies that decrease pulmonary Q or its heterogeneity may prevent pulmonary vascular injury in patients with sepsis-induced lung injury.

即使对肺的初始侮辱是弥漫的，ARDS也是斑点的，但是损伤的空间分布和潜在介体尚未得到充分探索。 血管通透性增加对于ARD的发病机理至关重要，区域差异可能导致异质性肺损伤。 我们的第一个假设是，蛋白质泄漏的速率在内毒素血症期间在整个肺部有所不同，并且具有非随机空间分布。 我们将在1.0 cm3肺部的内毒素猪中测量白蛋白泄漏的速率，以表征其空间分布，并验证泄漏率作为局部组织学损伤的测量。 观察到的泄漏率的空间分布将表明蛋白质泄漏的介质具有相似的空间分布。 我们的第二个假设是，区域肺血流（Q）的差异导致血管通透性和蛋白质泄漏的局部差异。 我们将对Q，白蛋白泄漏速率和等离子体体积（CSA [CSA]的替代物进行高分辨率测量值，以评估区域Q和白蛋白泄漏速率之间的相关性，并确定Q对血管渗透性或毛细血管表面积的影响解释。 我们的第三个假设是，内毒素血症期间区域Q的变异性有所增加，区域Q的重新分布有助于通风/灌注（V/Q）不等式，而不是由低氧肺血管收缩引起。我们将在内毒素血症之前和期间对区域V和Q进行高分辨率测量，并量化其变异性，空间分布和V/Q匹配的变化。表征蛋白质泄漏的区域差异是理解肺损伤异质性和非心脏病肺水肿的潜在介体的重要第一步。 如果高区域血流或相关的微血管压力会增加内毒素血症期间血管渗透性，则降低肺Q或其异质性的策略可能会预防败血症诱发的肺损伤患者的肺血管损伤。