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: 7185530
• 负责人: Marcos F Vidal Melo
• 金额: $ 43.16万
• 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/7185530
• 关键词: Acute; Acute Lung Injury; Animal Model; Animals; Area; Breathing; Cells; Clinical Data; Condition; 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; Invasive; 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; Thinking; Time; Tracer; Translating; United States; Validation; Ventilator; Ventilator-induced lung injury; base; clinical application; clinically relevant; concept; day; density; glucose uptake; in vivo; insight; lung imaging; lung injury; neutrophil; pre-clinical; prevent; tool

DESCRIPTION (provided by applicant): 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 (2-4 h) 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.

描述（由申请人提供）：机械通气设置是人类急性肺损伤（ALI）结局的主要因素，在美国，每年每10万居民中至少有137例患者接受机械通气治疗。该项目的长期目标是开发和应用正电子发射断层扫描（PET）技术来阐明ALI的产生机制，并改进评估、预防和治疗这种疾病的方法。肺膨胀的不均一性、相关的机械应力和嗜酸性炎症之间的关系被认为是呼吸机诱导的肺损伤（VILI）发病机制的核心。然而，关于VILI的几个公认概念是基于体外、小动物或理论模型的急性（2-4小时）均质制剂的外推，并用于解释人类呼吸机相关肺损伤的异质性、多因素和进行性（小时至天）性质。PET成像提供了在人体和大型动物体内评估机械通气引起的局部炎症和气体交换功能障碍的决定因素的工具。本研究的主要目的是：1）通过比较中性粒细胞减少绵羊和正常绵羊暴露于单肺VILI后两肺18F-FDG摄取的差异，评价中性粒细胞对肺局部18F-FDG摄取显像信号的贡献; 2）评估在不均匀扩张的肺中局部潮气体积应变和局部18F-FDG摄取之间的关系，作为炎症的量度，3）在存在和不存在内毒素血症的情况下，在18F-FDG摄取、潮气体积应变和气体交换功能障碍之间的区域关系中，量化由肺扩张的异质性引起的变化。将对绵羊模型进行研究，以模拟人类肺功能障碍和损伤的垂直依赖性，这在孤立的细胞或小型哺乳动物中基本上是不存在的。将使用PET成像研究肺功能和炎症的局部和时间变化：（a）静脉内（iv）18 F-FDG以量化嗜酸性炎症;（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。我们期望该项目将推进ALI的功能性肺成像，带来对ALI新机制的见解，产生将肺部PET成像转化为临床应用所需的临床前数据，并提供开发和测试合理方法的工具，以针对患者的机械治疗管理。