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

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL084922-01
Application #
7231245
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Project Start
2006-12-01
Project End
2011-11-30
Budget Start
2006-12-01
Budget End
2007-12-31
Support Year
1
Fiscal Year
2007
Total Cost
$424,143
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
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
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
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
Berk, David R; Bentley, Danette D; Bayliss, Susan J et al. (2012) Cutis laxa: a review. J Am Acad Dermatol 66:842.e1-17

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