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

描述(由申请人提供)：机械通气设置是影响人类急性肺损伤(ALI)预后的主要因素，在美国，每年每10万名居民中至少有137名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，以阐明ALI的发生机制，并提出评估、预防和治疗这种疾病的方法。肺扩张的异质性、相关的机械应力和中性粒细胞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，一些公认的关于VILI的概念是基于来自体外、小动物或理论模型的急性(2-4小时)均一制剂的推断，并被用来解释人类呼吸机相关肺损伤的异质性、多因素和进行性(几小时到几天)。PET成像提供了在活体内评估在人类和大型动物中，由机械通气产生的局部炎症和气体交换障碍的决定因素的工具。该项目包括3个具体目标：1)通过比较暴露于单肺VILI的完整和中性粒细胞耗竭的绵羊双肺之间的18F-FDG摄取，评估中性粒细胞对局部肺18F-FDG摄取成像信号的贡献；2)评估局部潮气量应变和局部18F-FDG摄取之间的关系，作为衡量炎症的指标，在人类被认为安全的通风环境下，并评估局部18F-FDG摄取是否与由此导致的局部气体交换功能障碍相关；3)在存在和不存在内毒素血症的情况下，量化18F-FDG摄取、潮气量应变和气体交换功能障碍之间的区域关系中肺扩张的异质性所引起的变化。将在绵羊模型上进行研究，以模拟人类肺功能障碍和损伤的垂直依赖性，这在分离的细胞或小型哺乳动物中基本上是不存在的。将通过PET成像研究肺功能和炎症的局部和时间变化：(A)静脉注射(Iv)18F-FDG以量化中性炎症；(B)静脉注射13N-N(13NN)-生理盐水以测量区域血流、通气量和分流；(C)吸入13NN以测量机械通气期间气体含量的动态变化。我们期待该项目将推进ALI的功能肺成像，为ALI的新机制带来洞察力，产生将肺部PET成像转化为临床应用所需的临床前数据，并为开发和测试针对患者特定机械通气管理的合理方法提供工具。

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.