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

呼吸机所致肺损伤局部炎症和功能的 PET 成像

• 批准号: 7544490
• 负责人: Marcos F Vidal Melo
• 金额: $ 43.54万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-10 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544490
• 关键词: Acute; Acute Lung Injury; Animal Model; Animals; Area; Breathing; Cells; Clinical Data; Deoxyglucose; Dependence; Disease; Endotoxemia; Environmental air flow; Force of Gravity; Functional disorder; Gases; Glucose; Goals; Heterogeneity; Hour; Human; Human Characteristics; Image; Imaging Techniques; In Vitro; Inflammation; Inflammatory; Injury; Intravenous; Label; Lead; Link; Lung; Mammals; Measurement; Measures; Mechanical Stress; Mechanical ventilation; Mechanics; Methods; Modeling; Nitrogen; Outcome; Pathogenesis; Patients; Perfusion; Positron-Emission Tomography; Preparation; Process; Regional Perfusion; Research Personnel; Respiratory physiology; Saline; Sheep; Shunt Device; Signal Transduction; Simulate; Stimulus; Structure; Techniques; Testing; Theoretical model; Time; Tracer; Translating; United States; Validation; Ventilator; Ventilator-induced lung injury; base; clinical application; clinically relevant; density; glucose uptake; in vivo; insight; lung imaging; lung injury; neutrophil; pre-clinical; prevent; tool

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.

机械通气设置是影响人类急性肺损伤(ALI)预后的主要因素，至少 在美国，每年每10万名居民中就有137名患者接受机械通风治疗。 该项目的长期目标是开发和应用正电子发射断层扫描技术 阐明ALI的发生机制，提出评估、预防和治疗ALI的方法 条件。肺扩张的非均质性及其相关机械应力与肺功能的关系 中性粒细胞炎症被认为是呼吸机所致肺损伤的核心发病机制。 (Vili)。然而，关于VILI的一些公认的概念是基于急性(2-4小时)的推断 来自体外、小动物或理论模型的均质制剂，用于解释 人类呼吸机相关肺的异质性、多因素和渐进性(几小时到几天) 受伤。PET成像提供了在活体内评估在人类和大型动物中的决定因素的工具 机械通气引起的局部炎症和气体交换功能障碍。该项目 包括3个具体目标：1)评估中性粒细胞对局部肺18F-氟代脱氧的贡献。 比较正常和正常双肺葡萄糖(18F-FDG)摄取显像信号 中性粒细胞耗竭绵羊暴露于单肺VILI；2)评估区域潮汐的关系 体积应变和局部18F-FDG摄取，作为炎症的衡量标准 在被认为对人体安全的呼吸机环境下，扩张肺，并评估局部18F-FDG 摄取与由此导致的区域气体交换功能障碍相关；3)量化由以下因素引起的变化 肺扩张的异质性在18F-FDG摄取与潮气量应变之间的区域关系中的作用 以及气体交换功能障碍，内毒素血症的存在和不存在。我们会进行研究 在绵羊模型上模拟人类肺功能障碍和损伤的垂直依赖性，这是 在孤立的细胞或小型哺乳动物中基本上不存在。肺功能的地形图和时间变化 炎症将用PET成像进行研究：(A)静脉注射(Iv)18F-FDG以定量中性粒细胞 炎症；(B)静脉注射13N-N(13NN)-生理盐水，以测量局部灌注、通风和分流；以及(C) 吸入13NN以测量机械通气过程中气体含量的动态变化。我们预计， 该项目将推进ALI的功能肺成像，为ALI的新机制带来见解，并产生所需的产量 将肺部PET成像转化为临床应用的临床前数据，并提供开发工具 以及测试针对患者的机械通气管理的合理方法。