PET Imaging of Local Inflammation and Function in Ventilator Induced Lung Injury

机械通气装置是人类急性肺损伤（ALI）预后的主要因素， 在美国，每年每10万居民中有137名患者接受机械通气治疗。 本项目的长期目标是发展和应用正电子发射断层扫描技术 (PET)阐明产生ALI的机制，并提出评估、预防和治疗ALI的方法， 条件肺扩张不均匀性、相关机械应力和 嗜酸性炎症被认为是呼吸机诱导的肺损伤发病机制的核心 （VILLI）.然而，几个公认的VILI概念是基于急性（2- 4小时）外推的 从体外，小动物或理论模型的均匀制剂，并用于解释 人类呼吸机相关肺的异质性、多因素和进展性（小时至天）性质 损伤PET成像提供了在人体和大型动物体内评估以下因素的工具： 机械通气引起的局部炎症和气体交换功能障碍。项目 包括3个具体目标：1）评估中性粒细胞对局部肺18F-氟脱氧- 葡萄糖（18F-FDG）摄取成像信号，通过比较完整肺和正常肺之间的18F-FDG摄取， 中性粒细胞耗竭绵羊暴露于单肺VILI; 2）评估区域性潮气量与局部性肺损伤的关系。 体积应变和局部18F-FDG摄取，作为炎症的测量，在一个不均匀的， 扩张肺，在实验室环境下被认为对人类是安全的，并评估区域18F-FDG是否 摄取与由此产生的区域气体交换功能障碍相关; 3）量化由 18F-FDG摄取、潮气体积应变与肺扩张的区域关系中的异质性 和气体交换功能障碍，无论是否存在内毒素血症。将进行研究 在绵羊模型上模拟人类肺功能障碍和损伤的垂直依赖性， 在分离的细胞或小型哺乳动物中基本上不存在。肺功能的局部和时间变化 和炎症将通过PET成像进行研究：（a）静脉内（iv）18F-FDG以定量嗜酸性粒细胞 炎症;（B）iv 13 N-氮（13 NN）-盐水以测量区域灌注、通气和分流;和（c） 吸入13 NN以测量机械通气期间气体含量的动态变化。我们预计 该项目将推进ALI的功能性肺成像，带来对ALI新机制的见解， 临床前数据将肺部PET成像转化为临床应用，并为开发 并测试针对患者的机械治疗管理的合理方法。

Mechanical ventilatory settings are a major factor for outcome in human acute lung injury (ALI) and at least 137 patients per 100,000 residents are treated with mechanical ventilation every year in the United States. The long-term goal of this project is to develop and apply techniques of Positron Emission Tomography (PET) to elucidate mechanisms producing ALI and to advance methods to assess, prevent, and treat this condition. The relationship between heterogeneity of lung expansion, associated mechanical stresses and neutrophilic inflammation, are thought to be central to the pathogenesis of ventilator induced lung injury (VILI). However, several accepted concepts on VILI are based on extrapolations from acute (2-4h) homogeneous preparations from in vitro, small animal, or theoretical models, and used to explain the heterogeneous, multifactorial and progressive (hours to days) nature of human ventilator-associated lung injury. PET imaging offers the tools to assess in vivo, in humans and large animals, the determinants of regional inflammation and gas exchange dysfunction produced by mechanical ventilation. The project consists of 3 specific aims: 1) To assess the contribution of neutrophils to the regional lung 18F-fluorodeoxy- glucose (18F-FDG) uptake imaging signal by comparing 18F-FDG uptake between both lungs of intact and neutrophil depleted sheep exposed to single lung VILI; 2) To assess the relationship between regional tidal volumetric strain and regional 18F-FDG uptake, as a measure of inflammation, in a heterogeneously expanding lung, under ventilatory settings deemed 'safe1 in humans, and evaluate whether regional 18F-FDG uptake correlates with the resulting regional gas exchange dysfunction; 3) To quantify changes caused by heterogeneity in lung expansion in the regional relationships between 18F-FDG uptake, tidal volumetric strain and gas exchange dysfunction, both in the presence and absence of endotoxemia. Studies will be conducted on sheep models to simulate the vertical dependence of lung dysfunction and injury in humans, which is essentially absent in isolated cells or small mammals. Topographical and temporal changes in lung function and inflammation will be studied with PET imaging of: (a) intravenous (iv)18F-FDG to quantify neutrophilic inflammation; (b) iv 13N-nitrogen (13NN)-saline to measure regional perfusion, ventilation, and shunt; and (c) inhaled 13NN to measure dynamic changes in gas content during mechanical ventilation. We expect that the project will advance functional lung imaging for ALI,bring insights on new mechanisms of ALI,yield needed pre-clinical data to translate PET imaging of the lung into clinical application, and provide tools for developing and testing rational approaches to patient-specific mechanical ventilatory management.