Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and is a risk factor for lung cancer development. COPD encompasses both emphysema and chronic bronchitis, the pathogenesis of which are unclear. In this dissertation, I leveraged genome-wide gene-expression studies of emphysema and lung cancer to investigate pathogenesis and carcinogenesis in COPD. Tobacco smoke is the primary cause of emphysema. The most severe form is also associated with alpha1-antitrypsin deficiency (AATD) resulting from a mutation. In this study, I leveraged multiple lung samples from patients with emphysema, with or without AATD. While genes involved in tissue repair decreased with emphysema severity, the unfolded protein response (UPR) was uniquely changed in AATD lungs. AATD may play multiple roles in emphysema and UPR activation suggests AAT replacement therapy may be insufficient to treat this form of emphysema. Emphysema is a progressive disease, and the mean linear intercept (Lm) can serve as a surrogate of progression. I evaluated whether Lm increases in non-diseased lungs may represent similar processes to those occurring in emphysema, and could offer insight into early stages of disease or homeostasis. Genes involved in tissue repair increased with Lm in controls but decreased in disease. Tissue repair processes may be active in even the non-insulted lung, suggesting their activity is necessary for lung homeostasis and their deficiency may drive emphysema progression. Finally, COPD patients are at increased lung cancer risk, and transcriptomic changes common to both diseases could explain this risk. In both COPD and lung cancer, I discovered that H3K27Me3 regulated genes are repressed, and that the methyltransferase responsible for H3K27me3, EZH2, is induced. H3K27Me3, an oncogenic histone modification, may drive carcinogenesis and pathogenesis in COPD. Though usual and AATD emphysema share transcriptomic signatures associated with tissue repair, which may be active in the normal homeostatic lung, the UPR changes in AATD emphysema only; successful therapeutic strategies in emphysema will need to account for this difference. In COPD, H3K27Me3 may play a role in both pathogenesis and carcinogenesis, making it an attractive target for therapeutic interventions, but one that would need further augmentation in AATD. / 2019-11-01T00:00:00Z

Chronic pulmonary diseases include a wide range of illnesses that differ in etiology, prevalence, symptomatology and available therapy. A common link among these illnesses is their impact on patients’ vital function of breathing, high symptom burden and significantly impaired quality of life. This dissertation research evaluates disease severity, symptom burden and health behaviors of patients with three different chronic pulmonary conditions. First, alpha-1 antitrypsin deficiency (AATD) is an inherited condition that typically is associated with an increased risk of early onset pulmonary emphysema. This study examines differences in demographic, health, and behavioral characteristics and compares clinical outcomes and health related behaviors and attitudes between two severe genotypes of AATD - ZZ and SZ. The findings of the study suggest that patients with SZ genotype and less severe form of deficiency report higher number of exacerbations, comorbidities, as well as unhealthy behaviors such as lack of exercise and current smoking. In addition, individuals with the more severely deficient ZZ genotype are more adherent to disease management and prevention program recommendations and maintain a healthier lifestyle than individuals with SZ genotype. Second chronic lung disease examined in this research was chronic obstructive pulmonary disease (COPD), the fourth leading cause of death and second leading cause of disability in the United States. Prevalence and burden of cough and phlegm, two of the most common symptoms of the COPD, were assessed among participants of the COPD Foundation’s Patient-Powered Research Network (COPD PPRN). In addition, association between patient-reported levels of phlegm and cough, clinical outcomes and patients’ quality of life were evaluated. Participants’ quality of life was assessed using Patient Reported Outcome Measurement Information System instrument PROMIS-29. Association between changes in symptom severity over time and patient-reported quality of life were examined. Findings of this study indicated that severity of cough and phlegm were associated with higher number of exacerbations, greater dyspnea, and worsened patient-reported quality of life including physical and social functioning. Improvement in cough and phlegm severity over time was associated with better patient-reported quality of life. Third pulmonary illness described in this dissertation is non-cystic fibrosis bronchiectasis (NCFB), a rare and etiologically diverse condition characterized by dilated bronchi, poor mucus clearance and susceptibility to bacterial infection. Association between presence of Pseudomonas aeruginosa (PA), one of the most frequently isolated pathogens in patients with NCFFB, and disease severity was assessed utilizing enrollment data from the Bronchiectasis and NTM Research Registry (BRR). NCFB disease severity was evaluated using modified versions of validated in large international cohorts instruments, the Bronchiectasis Severity Index (BSI) and FACED. The findings of this study indicate that PA infection is common in NCFB patients, and presence of PA in patients’ sputum is associated with having moderate and high severity of bronchiectasis. In addition, the results of this study suggest that the two severity assessment instruments classify patients with NCFB differently which may be attributed to a greater number of severity markers utilized in the calculation of the BSI compared to FACED. In conclusion, the proposed dissertation aims to enhance understanding of differences in health outcomes between genotypes of AATD within AlphaNet registry, and to guide future health-promoting behaviors. It highlights the burden of common symptoms such as cough and phlegm in patients with COPD within COPD PPRN and their association with patients’ quality of life. In addition, it introduces modified indices of NCFB severity and emphasizes high burden of the disease in patients with presence of PA within the US BRR.