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.
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