Advisory Committee Chair
S Vamsee Raju
Advisory Committee Members
Michelle V Fanucchi
Amit Gaggar
Robin Lester
Bradford Woodworth
Document Type
Dissertation
Date of Award
2019
Degree Name by School
Doctor of Public Health (DrPH) School of Public Health
Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality around the world. Cigarette smoking is a leading cause of COPD; similarly, individuals exposed to secondhand smoke (SHS) are also vulnerable to COPD and other airway diseases; however, distinct molecular mechanisms involved in SHS-induced lung effects that result in COPD are poorly understood. Mucociliary clearance (MCC) is a primary lung defense against inhaled particulate matter and pathogens. Thus, understanding how inhaled irritants such as SHS disrupt MCC will promote improved scientific understanding and better public health initiatives to prevent respiratory illnesses. Using a variety of in vitro and in vivo models, we demonstrate SHS impairs cystic fibrosis transmembrane conductance regulator (CFTR), that when defective causes cystic fibrosis lung disease. CFTR dysfunction by SHS caused a pronounced decrease in airway surface hydration and MCC. Data implicated acrolein, a reactive aldehyde was increased in SHS and likely played a key role in CFTR dysfunction. More importantly treatment with antioxidant N-acetylcysteine reduced free acrolein and protected CFTR function and MCC in mice affected by SHS exposure. While use of electronic cigarettes (e-cigarettes) has increased substantially, scientific investigation and regulation enforcement of these products is lagging. Systemic investigation of e-cigarette effects on lung function is complicated by the diversity of e-liquid composition and device designs. Hence, we gather information regarding how MCC defense is affected by vaporized nicotine, the principle addictive component that’s common to all e-cigarettes, to draw conclusions regarding its long-term safety. Using three different laboratory models, human bronchial epithelial cells, rats, and ferrets, we found nicotine alone causes CFTR dysfunction resulting in diminished airway surface hydration and delayed MCC. We also discovered CFTR dysfunction by nicotine is mediated specifically via non-neuronal alpha7-nicotinic acetylcholine receptors (α7-nAChR). Interestingly, α7-nAChR pharmacologic activation prevented nicotine induced defects in CFTR function and MCC in vivo. Moreover, we demonstrate α7-nAChR agonist GTS21 can reverse CFTR dysfunction in rat model of smoking induced COPD. Overall, this dissertation research establishes harmful effects of SHS and emerging nicotine products on respiratory health and has potential to shape future endeavors of regulatory bodies and public health community.
Recommended Citation
Rasmussen, Lawrence, "Impact Of Environmental Exposures On Respiratory Health" (2019). All ETDs from UAB. 2793.
https://digitalcommons.library.uab.edu/etd-collection/2793