Regional Tidal Lung Strain and Neutrophilic Inflammation in Early Lung Injury

描述（由申请人提供）：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，估计每年有790,257例涉及机械通气的住院治疗，费用为270亿美元，占所有医院费用的12%。我们的长期目标是了解产生VALI的机制，并提出检测、预防和治疗VALI的方法。机械通气时潮汐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，目前尚不清楚在细胞培养和小动物中主要研究的潮汐菌株的炎症反应如何转化为机械通气的大型动物和人肺。正电子发射断层扫描(PET)/计算机断层扫描（CT）技术与先进的图像分析相结合，提供了一种新的方法来量化区域潮汐容量肺应变（CT）和中性粒细胞炎症（PET与葡萄糖类似物示踪剂2-脱氧-2-[18F]氟- d -葡萄糖，FDG）。我们的初步数据表明，在发炎（内毒素暴露）的肺中，fdg摄取与潮汐容量应变有很强的线性关系。这些数据还表明，FDG摄取的局部变化可以在发生重大实质损伤之前发现肺损伤的早期迹象。针对预防，我们建议使用目前推荐的通气策略研究非均质扩张、中度炎症肺的早期机械通气。我们的中心假设是，区域性肺中性粒细胞炎症和潜在的代谢和转录变化直接依赖于区域性肺容量应变，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（目的1和2）的绵羊模型以及机械通气患者（目的3）中验证这一假设，目的有三个：(1)评估潮肺容量应变对肺FDG动力学、组织中性粒细胞炎症和中性粒细胞基因表达的区域影响；(2)探讨肺损伤24h时局部实质损伤、中性粒细胞炎症和肺功能障碍与FDG-PET测定的早期（6h）局部细胞代谢活性的相关性；(3)脓毒症患者机械通气后48h内，建立肺中性粒细胞炎症与局部肺劳损及随后肺功能障碍程度的关系。如果我们的假设是正确的，那么局部肺劳损将被证明与中性粒细胞炎症呈线性关系，挑战目前“安全”阈值的概念，超过该阈值会导致肺水肿和炎症，并影响在重症监护病房和手术室中如何进行机械通气。此外，通过FDG摄取增加确定的早期中性粒细胞炎症将与随后的实质损伤和肺功能障碍以及临床恶化相关。这些发现将确立FDG-PET/CT作为VALI发展的早期生物标志物，有助于预测功能恶化和肺损伤。

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.