Regional Tidal Lung Strain and Neutrophilic Inflammation in Early Lung Injury

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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.