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 (2-4h) 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086827-05
Application #
8002084
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Harabin, Andrea L
Project Start
2007-01-10
Project End
2013-12-31
Budget Start
2011-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$435,306
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Wellman, Tyler J; de Prost, Nicolas; Tucci, Mauro et al. (2016) Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity. Anesthesiology 125:992-1004
Wellman, Tyler J; Winkler, Tilo; Vidal Melo, Marcos F (2015) Modeling of Tracer Transport Delays for Improved Quantification of Regional Pulmonary ¹⁸F-FDG Kinetics, Vascular Transit Times, and Perfusion. Ann Biomed Eng 43:2722-34
Wellman, Tyler J; Winkler, Tilo; Costa, Eduardo L V et al. (2014) Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep*. Crit Care Med 42:e491-500
de Prost, Nicolas; Feng, Yan; Wellman, Tyler et al. (2014) 18F-FDG kinetics parameters depend on the mechanism of injury in early experimental acute respiratory distress syndrome. J Nucl Med 55:1871-7
Farhan, Hassan; Moreno-Duarte, Ingrid; McLean, Duncan et al. (2014) Residual Paralysis: Does it Influence Outcome After Ambulatory Surgery? Curr Anesthesiol Rep 4:290-302
Eikermann, Matthias; Vidal Melo, Marcos F (2014) Therapeutic range of spontaneous breathing during mechanical ventilation. Anesthesiology 120:536-9
de Prost, Nicolas; Costa, Eduardo L; Wellman, Tyler et al. (2013) Effects of ventilation strategy on distribution of lung inflammatory cell activity. Crit Care 17:R175
Tucci, Mauro R; Costa, Eduardo L V; Wellman, Tyler J et al. (2013) Regional lung derecruitment and inflammation during 16 hours of mechanical ventilation in supine healthy sheep. Anesthesiology 119:156-65
Saha, Dalia; Takahashi, Kazue; de Prost, Nicolas et al. (2013) Micro-autoradiographic assessment of cell types contributing to 2-deoxy-2-[(18)F]fluoro-D-glucose uptake during ventilator-induced and endotoxemic lung injury. Mol Imaging Biol 15:19-27
Vidal Melo, Marcos F; Musch, Guido; Kaczka, David W (2012) Pulmonary pathophysiology and lung mechanics in anesthesiology: a case-based overview. Anesthesiol Clin 30:759-84

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