Non-invasive, regional assessment of lung function has the potential to markedly enhance early diagnosis and management of disease, to accelerate drug discovery and trials, and to provide fundamental insights into the root causes of disease. In this proposal, we aim to address a fundamental question of emphysema pathogenesis thorough a systematic study of lung function and structure using techniques developed over the first funding cycle. These techniques include measurements of pulmonary ventilation and perfusion, alveolar oxygen tension, and a sensitive measure of lung microstructure using hyperpolarized magnetic tracers, as well as several well-established methods in pulmonary medicine. The proposed research is designed specifically to corroborate or refute a molecular model of emphysema progression that is currently under widespread debate. Despite extensive investigation, it is still not clear which of the numerous and varied presentations of emphysema corresponds to the fundamental cause of the disease, or even if one principal cause can be identified. Nonetheless, a large body of current research suggests that altered expression of one or more mediators of angiogenesis may be the first step in the disease. This alteration degrades the capillary endothelium's ability to repair itself, resulting in cell death, reduced perfusion, and ultimately tissue destruction. Although in vivo imaging methods cannot replace the powerful molecular techniques in use today, they can provide a more complete picture of the action of disease or therapy on the body. In this study, we first demonstrate a comprehensive, self-consistent, and validated set of pulmonary measurements and evaluate sensitivity to disease. We then apply these measurements to three animal models of emphysema in order to evaluate time ordering and spatial correlation of the various aspects of pulmonary dysfunction. By comparing these measurements to testable predictions of the disease model, we hope to elucidate the first stages of this devastating disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Gan, Weiniu
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University of Pennsylvania
Schools of Medicine
United States
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Siddiqui, Sarmad; Xin, Yi; Emami, Kiarash et al. (2014) Hyperpolarized (3)He diffusion MRI and histology of secreted frizzled related protein-1 (SFRP1) deficient lungs in a Murine model. Magn Reson Imaging 32:535-40
Cereda, Maurizio; Xin, Yi; Kadlecek, Stephen et al. (2014) Hyperpolarized gas diffusion MRI for the study of atelectasis and acute respiratory distress syndrome. NMR Biomed 27:1468-78
Cereda, Maurizio; Xin, Yi; Emami, Kiarash et al. (2013) Positive end-expiratory pressure increments during anesthesia in normal lung result in hysteresis and greater numbers of smaller aerated airspaces. Anesthesiology 119:1402-9
Cereda, Maurizio; Emami, Kiarash; Xin, Yi et al. (2013) Imaging the interaction of atelectasis and overdistension in surfactant-depleted lungs. Crit Care Med 41:527-35
Ishii, Masaru; Emami, Kiarash; Xin, Yi et al. (2012) Regional function-structure relationships in lungs of an elastase murine model of emphysema. J Appl Physiol 112:135-48
Emami, Kiarash; Chia, Elaine; Kadlecek, Stephen et al. (2011) Regional correlation of emphysematous changes in lung function and structure: a comparison between pulmonary function testing and hyperpolarized MRI metrics. J Appl Physiol 110:225-35
Cereda, Maurizio; Emami, Kiarash; Kadlecek, Stephen et al. (2011) Quantitative imaging of alveolar recruitment with hyperpolarized gas MRI during mechanical ventilation. J Appl Physiol 110:499-511
Stephen, Michael J; Emami, Kiarash; Woodburn, John M et al. (2010) Quantitative assessment of lung ventilation and microstructure in an animal model of idiopathic pulmonary fibrosis using hyperpolarized gas MRI. Acad Radiol 17:1433-43
Emami, Kiarash; Kadlecek, Stephen J; Woodburn, John M et al. (2010) Improved technique for measurement of regional fractional ventilation by hyperpolarized 3He MRI. Magn Reson Med 63:137-50
Yu, Jiangsheng; Law, Michelle; Kadlecek, Stephen et al. (2009) Simultaneous measurement of pulmonary partial pressure of oxygen and apparent diffusion coefficient by hyperpolarized 3He MRI. Magn Reson Med 61:1015-21

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