Regional Tidal Lung Strain and Neutrophilic Inflammation in Early Lung Injury

描述(申请人提供)：呼吸机相关性肺损伤(VALI)是一种炎症性疾病，可增加机械通气患者的发病率和死亡率。在美国，据估计，每年有790,257人因机械通风而住院，费用为270亿美元，占所有医院费用的12%。我们的长期目标是S了解VALI的产生机制，并提出检测、预防和治疗的方法。潮气性肺劳损引起的中性粒细胞炎症是VALI发病的关键过程。然而，目前尚不清楚对潮汐应变的炎症反应主要是在细胞培养和小动物中研究的，如何转化为机械通风的大动物和人类肺。正电子发射断层扫描(PET)/计算机断层扫描(CT)技术结合先进的图像分析技术提供了一种新的方法来量化区域性潮气量肺应变(CT)和中性粒细胞炎症(使用葡萄糖类似示踪剂2-脱氧-2-[18F]氟-D-葡萄糖，FDG的PET)。我们的初步数据表明，在炎症(内毒素暴露)的肺中，FDG摄取与潮气容量应变有很强的线性相关性。这些数据还表明，FDG摄取的局部变化可以在出现明显的实质损伤之前发现肺损伤的早期迹象。为了预防，我们建议使用目前推荐的机械通气策略来研究异质性扩张、中度炎症的肺的早期机械通气阶段。我们的中心假设是，局部肺中性粒细胞炎症和潜在的代谢和转录变化直接依赖于局部容量肺应变，并先于肺实质损伤。我们将在内毒素血症和24小时机械通气(目标1和2)和机械通气患者(目标3)的绵羊模型中验证这一假设，目的有三：(1)评估潮汐肺容量应变对肺FDG动力学、组织中性粒细胞炎症和中性粒细胞基因表达的局部影响；(2)确定肺损伤后24小时局部实质损伤、中性粒细胞炎症和肺功能障碍与早期(6小时)局部细胞代谢活动的相关性；(3)在脓毒症患者机械通气的前48小时内，建立肺中性粒细胞炎症与局部肺劳损及随后的肺功能障碍程度之间的关系。如果我们的假设是正确的，区域性肺应变将被证明与中性粒细胞炎症呈线性相关，挑战当前的“安全”阈值的概念，超过该阈值会导致肺水肿和炎症，并影响重症监护病房和手术室的机械通风。此外，以FDG摄取增加为特征的早期中性粒细胞炎症与随后的实质损害和肺功能障碍以及临床恶化相关。这些发现将使FDG-PET/CT成为VALI发生的早期生物标志物，有助于预测VALI的功能恶化和肺损伤。

DESCRIPTION (provided by applicant): Ventilator-associated lung injury (VALI) is an inflammatory condition that can increase the morbidity and mortality of mechanically ventilated patients. In the US, estimates suggest 790,257 hospitalizations/year involving mechanical ventilation, with costs of $27 billion, representing 12% of all hospital costs. Our long-term goal s to understand the mechanisms producing VALI, and to advance methods to detect, prevent, and treat it. Neutrophilic inflammation produced by tidal lung strain during mechanical ventilation is key process in the pathogenesis of VALI. However, it is unclear how that inflammatory response to tidal strain predominantly studied in cell cultures and small animals translates to the mechanically ventilated large animal and human lung. Positron Emission Tomography (PET)/Computed Tomography (CT) techniques coupled with advanced image analysis provide a novel means to quantify regional tidal volumetric lung strain (CT) and neutrophilic inflammation (PET with the glucose analogue tracer 2-Deoxy-2-[18F]Fluoro-D-Glucose, FDG). Our preliminary data indicate a strong linear dependence of FDG-uptake on tidal volumetric strain in inflamed (endotoxin exposed) lungs. These data also suggest that local changes in FDG uptake can detect early signs of lung injury before significant parenchymal damage develops. Aiming at prevention, we propose to study the early stages of mechanical ventilation of the heterogeneously expanding, moderately inflamed lung using currently recommended ventilatory strategies. Our central hypothesis is that regional lung neutrophilic inflammation and underlying metabolic and transcriptional changes depend directly on regional volumetric lung strain, and precede lung parenchymal damage. We will test this hypothesis in sheep models of endotoxemia and 24 hours of mechanical ventilation (Aims 1 and 2) and mechanically ventilated patients (Aim 3) in three aims: (1) To assess the regional effects of tidal lung volumetric strain on pulmonary FDG kinetics, tissue neutrophilic inflammation, and neutrophil gene expression; (2) To ascertain the dependence of regional parenchymal damage, neutrophilic inflammation, and lung dysfunction at 24h of lung injury on earlier (6h) local cellular metabolic activity quantified with FDG-PET; and (3) Within the first 48h of mechanical ventilation in septic patients, to establish the relationship between pulmonary neutrophilic inflammation and regional lung strain as well as the ensuing degree of lung dysfunction. If our hypothesis is correct, regional lung strain will prove to be linearly related to neutrophilic inflammation, challenging current concepts of a "safe" threshold above which strain causes lung edema and inflammation, and influencing how mechanical ventilation is delivered in intensive care units and operating rooms. Additionally, early neutrophilic inflammation identified by increased FDG uptake will correlate with subsequent parenchymal damage and lung dysfunction as well as with clinical deterioration. Such findings would establish FDG-PET/CT as an early biomarker in the development of VALI, useful for the prediction of functional deterioration and lung injury.