Project Summary/ Abstract
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lungs that results in
airflow limitation; it affects 24 million adults in the United States, and is the third leading cause of death. Recent
studies challenge the paradigm that COPD is uniformly progressive, but the mechanisms that underlie distinct
trajectories of disease progression are not well understood. A major hurdle in the advancement of therapies that
alter the progression of disease is our inability to precisely phenotype individuals with variable disease trajectories;
reliable surrogate biomarkers to predict clinical progression in individual subjects are lacking. Furthermore, existing
pharmacotherapies have a modest impact on respiratory morbidity and fail to impact the rate of FEV1 decline.
These medications target airway tone and inflammation, and none directly target structural changes involving the
airways or alveolar remodeling (emphysema) that underlie FEV1 change. Thus, a major gap in understanding is
the identification of inter-dependent pathways of structural airway/alveolar remodeling that determine disease
progression which would inform more precise diagnostic and therapeutic strategies for COPD.
The origins of COPD are believed to be in the small conducting airways less than 2 mm in diameter but these
data are mostly cross-sectional. In addition, COPD is characterized by both airway remodeling and alveolar
destruction; it is likely that both processes contribute to disease initiation and progression. Our preliminary findings
suggest that disease progression occurs due to a complex interplay of structural changes in the lungs, both in the
parenchyma and in the airways, including mechanical stretch of normal parenchyma, distribution of emphysema,
and airway remodeling. Disease progression is not reflected entirely by FEV1 changes and progression of structural
disease is an important determinant of disease trajectory. Based on these findings, we hypothesize that structural
anatomic and mechanical factors in both the airway and alveolar compartments contribute to disease progression in
To test these hypotheses, we will analyze data from two large well-characterized cohorts (Genetic
Epidemiology of COPD, COPDGene, and Subpopulations and Intermediate Outcome Measures in COPD Study,
SPIROMICS) with 5-year follow-up with the following specific aims. Aim 1 of this application will be to determine
whether mechanically affected lung leads to initiation and progression of emphysema. In Aim 2, we will determine
whether the spatial distribution of emphysema influences disease progression. In Aim 3, we will determine whether
longitudinal changes in airway remodeling are associated with lung function decline.
The results will identify mechanisms of disease progression, establish novel imaging biomarkers, and help
create precise models that will allow development of more targeted therapies to attenuate disease progression.