Emphysema is one of the two major components of chronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States. No currently available treatment can meaningfully slow the progressive loss of lung function that occurs in COPD, and no treatment can restore lost lung function. Emphysema is destruction of lung tissue that results from damage that exceeds the ability of the lung to repair. Recent evidence suggests that lung repair processes are diminished in COPD and due, at least in part, to increased levels of prostaglandin E (PGE), an important inhibitor of mesenchymal cell-mediated repair and that PGE is over-produced by lung fibroblasts in patients with emphysema. Our clinical proposal will set the stage to evaluate inhibition of PGE production to treat emphysema. To justify a Phase 3 clinical efficacy trial, our proposed Phase 2 trial will determine if inhibition of PGE production can be achieved in the lung of patients with emphysema and will test whether this is associated with improvement in biomarkers of lung tissue repair and inflammation. Our secondary outcome measures will help determine sample size estimates for a Phase 3 trial. In addition, our methodology will quantify prostanoids in addition to PGE, allowing us to provide novel information about these important mediators in COPD. Finally, our study will take advantage of a unique subject cohort, prior participants in the COPDGene study. Careful assessment of lung structure and function using CT scan and pulmonary function testing were performed several years ago in COPDGene. Using the difference between these legacy data and the repeat measures proposed in our trial will allow us to determine the relationship between lower respiratory tract PGE levels and other inflammatory measures to the rate of emphysema progression. In the accompanying Ancillary Study, we will determine if alveolar macrophages also contribute to PGE over-production in COPD and will determine if PGD, a major macrophage product is also over-produced. Finally we will determine if the microRNA miR- 146a modulates prostaglandin production in macrophages as it does in fibroblasts and if gene polymorphisms in the miR-146a gene contribute to altered levels in COPD.
Current treatments neither meaningfully slow the loss of lung function nor restore lost function in emphysema. We propose to determine if inhibition of prostaglandin E production can be achieved in the lungs of emphysema patients and if this intervention leads to improvement in biomarkers of lung repair. This will set the stage for a Phase 3 study designed to improve lung repair and thereby alter the natural history of pulmonary emphysema.