The defining feature of chronic obstructive pulmonary disease (COPD) is irreversible airflow limitation measured during forced expiration. This results from a varying combination of increased airflow resistance in the small airways and decreased elastic recoil due to emphysematous destruction of lung tissue. We recently showed that significant obstruction of the small airways is present in the lungs of patients with advanced emphysema and that the inflammatory response in the peripheral lung tissue correlates with the severity of COPD as gauged by the GOLD classification scheme. Quantitative analysis of the inflammatory response found strong correlation with the level of lung infiltration by CD8+ T cells, B cells, and macrophages and suggested that these cell types may specially serve to drive the COPD phenotype. Using CT and 3He magnetic resonance imaging (3He MRI) to quantitatively assess regional differences in small airway obstruction and emphysematous destruction in severe COPD, our imaging group has found that regions of mild to moderate disease are found adjacent to sites of severe destruction or obstructive disease even in patients with GOLD 4-stage disease. We hypothesize that the different levels of lesion severity represent different stages in the pathogenesis of the lesions. Our active lung transplantation program, expertise in new imaging technologies and the ability to conduct quantitative analysis of the inflammatory response and tissue remodeling afford a unique opportunity to construct new criteria for assessment of COPD patients. We propose to investigate the pathogenesis of GOLD 4-stage COPD in patients awaiting lung transplant with the following Specific Aims: 1) To test the hypothesis that there is progression in both extent and severity of the inflammatory immune process in regions affected by moderate to severe degrees of emphysema and small airway disease, using morphologic analysis and quantitative immunopathology to characterize the inflammatory immune process. 2) To noninvasively quantify the regional extent and severity of disease separately in subjects with severe COPD using 3He MRI and high-resolution CT imaging. 3) To validate the in-vivo and ex-vivo imaging results in Aim II against the histology in Aim I in order to develop a new approach to quantifying both the extent and severity of emphysema and small airways disease within the lungs of individual patients with COPD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Yablonskiy, Dmitriy A; Sukstanskii, Alexander L; Quirk, James D (2017) Diffusion lung imaging with hyperpolarized gas MRI. NMR Biomed 30:
Schlabritz-Loutsevitch, N; Apostolakis-Kyrus, K; Krutilina, R et al. (2016) Pregnancy-driven cardiovascular maternal miR-29 plasticity in obesity. J Med Primatol 45:297-303
Wu, Kangyun; Byers, Derek E; Jin, Xiaohua et al. (2015) TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J Exp Med 212:681-97
Yablonskiy, Dmitriy A; Sukstanskii, Alexander L; Quirk, James D et al. (2014) Probing lung microstructure with hyperpolarized noble gas diffusion MRI: theoretical models and experimental results. Magn Reson Med 71:486-505
Coghlan, Meghan A; Shifren, Adrian; Huang, Howard J et al. (2014) Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations. BMJ Open Respir Res 1:e000057
Philippot, Quentin; Deslée, Gaëtan; Adair-Kirk, Tracy L et al. (2014) Increased iron sequestration in alveolar macrophages in chronic obstructive pulmonary disease. PLoS One 9:e96285
Lutey, Barbara A; Conradi, Susan H; Atkinson, Jeffrey J et al. (2013) Accurate measurement of small airways on low-dose thoracic CT scans in smokers. Chest 143:1321-1329
Magalotti, Selena; Gustafson, Tiffany P; Cao, Qian et al. (2013) Evaluation of inflammatory response to acute ischemia using near-infrared fluorescent reactive oxygen sensors. Mol Imaging Biol 15:423-30
Betsuyaku, Tomoko; Fuke, Satoshi; Inomata, Takashi et al. (2013) Bronchiolar epithelial catalase is diminished in smokers with mild COPD. Eur Respir J 42:42-53
Wang, Wei; Nguyen, Nguyet M; Agapov, Eugene et al. (2012) Monitoring in vivo changes in lung microstructure with ³He MRI in Sendai virus-infected mice. J Appl Physiol (1985) 112:1593-9

Showing the most recent 10 out of 48 publications