Regional Tidal Lung Strain and Neutrophilic Inflammation in Early Lung Injury

描述（由申请方提供）：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例住院治疗涉及机械通气，成本为270亿美元，占所有医院成本的12%。我们的长期目标是了解VALI的发生机制，并提出检测、预防和治疗VALI的方法。然而，目前还不清楚主要在细胞培养物和小动物中研究的对潮汐应变的炎症反应如何转化为机械通气的大型动物和人类肺。正电子发射断层扫描（PET）/计算机断层扫描（CT）技术与先进的图像分析相结合，提供了一种量化局部潮气量肺应变（CT）和嗜酸性炎症的新方法（PET与葡萄糖类似物示踪剂2-脱氧-2-[18 F]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摄取对潮气容积应变有很强的线性依赖性。这些数据还表明，FDG摄取的局部变化可以在显著的实质损伤发生之前检测到肺损伤的早期体征。针对预防，我们建议研究早期阶段的机械通气的不均匀扩大，中度发炎的肺使用目前推荐的治疗策略。我们的中心假设是，区域性肺嗜酸性炎症和潜在的代谢和转录变化直接依赖于区域体积肺应变，并先于肺实质损伤。我们将在绵羊内毒素血症模型和24小时机械通气中检验这一假设（1）评估潮气肺容积应变对肺FDG动力学、组织嗜中性粒细胞炎症和中性粒细胞基因表达的局部影响;（2）明确肺损伤24小时局部实质损害、嗜酸性炎症和肺功能障碍与早期（6小时）FDG-PET定量的局部细胞代谢活性的相关性;（3）脓毒症患者机械通气后48 h内，肺内嗜酸性炎症反应与局部肺劳损及肺功能损害程度的关系。如果我们的假设是正确的，局部肺应变将被证明是线性相关的嗜酸性炎症，挑战目前的概念，一个“安全”阈值以上的应变导致肺水肿和炎症，并影响如何在重症监护病房和手术室提供机械通气。此外，通过FDG摄取增加识别的早期嗜酸性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，可用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.