The role of epithelial cells in COPD

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease of the airways that results in the decline of lung function with patients having emphysema or chronic bronchitis pathologies and is responsible for 7% of global deaths per year. Smoking is the largest risk factor for causing COPD and COPD patients can experience exacerbations which is defined as worsening of the symptoms which often leads to hospitalizations. The strongest risk factors for exacerbations are bacterial or viral infections. Non-typeable haemophilus Influenzae (NTHi) and Rhinovirus (RV) in particular are associated with up to half of COPD exacerbations. The epithelium is the first line of defense against pathogens and responsible for keeping the microbiome in check. COPD patients have been shown to have a dysfunctional epithelium. In this thesis, I investigate the role of bronchial epithelial cells in healthy, smokers, and COPD patients to assess any difference in host immune responses and barrier integrity. They are examined under the context of an infection by the common pathogens that are found, NTHi and RV. In particular, I study type I and type III Interferon (IFN) production as well as the production of alarmins and pro-inflammatory cytokines. In addition, I assess the expression and spatial changes of Tight Junction (TJ) proteins Claudin (CLDN)-3, CLDN-4, and Junctional Adhesion Molecule A (JAM-A) in HBECs post-infection as well as barrier integrity. Finally, HBECs from basal and differentiated HBECs are infected and sequenced to capture gene expression of HBECs and assess for any differences. COPD human bronchial epithelial cells (HBECs) immune and anti-viral responses are dysregulated as well as TJ protein expression compared to healthy HBECs post-infection with either NTHi or RV16. NTHi infected COPD HBECs had significantly higher concentrations of IFNλ1 and an significant increase in TNFα but did not upregulate TJ molecules during infection unlike in healthy HBECs. Smoker and COPD HBECs however had significantly higher levels of all TJ proteins measured at basal levels compared to health HBECs. My RNA-seq data demonstrated that COPD HBECs express significantly higher amounts of inflammatory genes post-infection with NTHi compared to healthy HBECs and smoker HBECs upregulate anti-viral genes post-infection with NTHi in basal cultures. Together, the data shows that COPD HBECs behave differently than heathy HBECs and are dysfunctional as well as smoker HBECs post-infection in certain contexts.