Emphysema is a major medical problem in the US and worldwide. In this grant application we propose to develop non-invasive lung morphometry as an improved diagnostic of this debilitating disease. Our technique is based on diffusion MRI with hyperpolarized 3He gas and allows in vivo 3D tomographic estimation of the lung alveolar surface area, alveolar density, and acinar airway radii - parameters that have been used by lung physiologists for decades as the gold standard for quantifying emphysema but were previously only measurable through invasive lung biopsy. As part of the previous grant period, we obtained in vivo lung morphometry data on 30 subjects with known smoking histories in the early stages of emphysema. This data revealed very specific changes in lung morphometry which were not appreciated with conventional clinical tests, suggesting that our technique is a very sensitive tool for detecting early changes in the lung microstructure. The main goal of this Renewal Application is to extend the diagnostic potential of the in vivo lung morphometry technique for identifying structural changes in lung parenchyma to all stages of emphysema. To achieve this goal we will: (i) extend our current mathematical model of gas diffusion in lungs by incorporating the effects of progressive lung tissue destruction on 3He gas diffusion;(ii) non-invasively establish the baseline parameters of lung microstructure in healthy human subjects without smoking histories over a range of age categories;(iii) non-invasively characterize the changes in lung microstructure for subjects in the initial through advanced stages of emphysema;(iv) validate our technique against direct morphometric measurements. Overall, we propose to further develop and validate our advanced MRI techniques for imaging of the human lung as superior, specific characterization of emphysematous changes in lung, and apply these techniques to advance our understanding of the microstructural changes that occur in emphysema, across a wide range of age and disease stages. A comprehensive picture of the changes in lung microstructure at the alveolar level with emphysema progression will be elucidated, from the initial onset of alveolar deformation to the advanced stages, characterized by a dramatic loss of lung function. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and non-invasive in vivo biomarkers for monitoring drug efficacy in clinical trials.

Public Health Relevance

The main goal of this study is to further develop our advanced MRI technique for imaging of the human lung - in vivo lung morphometry - as a superior, more sensitive characterization of emphysematous changes, and apply this technique to advance our understanding of the changes in lung alveoli and airways that occur in emphysema, across a wide range of ages and disease stages. This technique is based on diffusion MRI with hyperpolarized 3He gas. The results will provide new clinical insights into emphysema progression, from the initial onset of the alveolar deformation to the final stages, characterized by dramatic loss of lung function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biomedical Imaging Technology Study Section (BMIT)
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Gan, Weiniu
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Washington University
Schools of Medicine
Saint Louis
United States
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Chang, Yulin V; Quirk, James D; Yablonskiy, Dmitriy A (2015) In vivo lung morphometry with accelerated hyperpolarized (3) He diffusion MRI: a preliminary study. Magn Reson Med 73:1609-14
Quirk, James D; Chang, Yulin V; Yablonskiy, Dmitriy A (2015) In vivo lung morphometry with hyperpolarized (3) He diffusion MRI: reproducibility and the role of diffusion-sensitizing gradient direction. Magn Reson Med 73:1252-7
Sukstanskii, Alexander L; Quirk, James D; Yablonskiy, Dmitriy A (2014) Probing lung microstructure with hyperpolarized 3He gradient echo MRI. NMR Biomed 27:1451-60
Pennati, Francesca; Quirk, James D; Yablonskiy, Dmitriy A et al. (2014) Assessment of regional lung function with multivolume (1)H MR imaging in health and obstructive lung disease: comparison with (3)He MR imaging. Radiology 273:580-90
Yablonskiy, Dmitriy A; Sukstanskii, Alexander L; Conradi, Mark S (2014) Commentary on "The influence of lung airways branching structure and diffusion time on measurements and models of short-range 3He gas MR diffusion". J Magn Reson 239:139-42
Sukstanskii, A L (2013) Exact analytical results for ADC with oscillating diffusion sensitizing gradients. J Magn Reson 234:135-40
Sukstanskii, A L; Yablonskiy, D A (2012) Lung morphometry with hyperpolarized 129Xe: theoretical background. Magn Reson Med 67:856-66
Hajari, A J; Yablonskiy, D A; Sukstanskii, A L et al. (2012) Morphometric changes in the human pulmonary acinus during inflation. J Appl Physiol 112:937-43
Wang, Wei; Nguyen, Nguyet M; Agapov, Eugene et al. (2012) Monitoring in vivo changes in lung microstructure with ýýHe MRI in Sendai virus-infected mice. J Appl Physiol (1985) 112:1593-9
Hajari, A J; Yablonskiy, D A; Quirk, J D et al. (2011) Imaging alveolar-duct geometry during expiration via ³He lung morphometry. J Appl Physiol (1985) 110:1448-54

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