Nicotine is the pharmacologically active/addictive compound in tobacco. As such, the lung serves as an ideal and efficient delivery route for nicotine absorption into the bloodstream where it can then cross the blood brain barrier and induce psychotropic effects on the brain. Recently, with the advent of electronic cigarettes (E- Cigs), people have begun inhaling purified nicotine in a liquid vehicle (typically vegetable glycerin/propylene glycol). While the effects of nicotine on the brain and cardiovascular system are well known, the effects of nicotine on the lung have been less studied. Mucus clearance is a major part of the lung's innate defense system and represents the first point of contact of the body with inhaled nicotine. Perturbations in CFTR- mediated ion transport, which is required for mucus hydration/clearance, or biochemical alterations to mucins impair this system, leaving the lung more prone to mucus accumulation/plugging and viral infections, as evidenced by cystic fibrosis and chronic bronchitis lung disease. Our preliminary data indicate that E-cig users have a drastically altered mucus proteome which is suggestive of immunosuppression. In vitro, we found that nicotine, acting through intracellular Ca2+ (i) dephosphorylated CFTR leading to CFTR inactivation and internalization to the endoplasmic reticulum and (ii) altered mucin rheology by directly interacting with mucins. Furthermore, our data also suggest that the normal ability of the airways to activate CFTR and secrete mucins to generate an ?airway flush? to remove inhaled viruses is impaired following nicotine exposure, which is predicted to lead to a failure to resolve common viral infections such as respiratory syncytial virus. We hypothesize therefore, that nicotine causes an immunosuppressed phenotype that leaves the lung more prone to viral exacerbations. Specifically, we propose that (i) nicotine-induced Ca2+ signaling leads to CFTR dephosphorylation and internalization to the endoplasmic reticulum (ii) altered mucus rheology and (iii) a failure to efficiently resolve viral infections. We shall study this hypothesis with the following specific aims:
Aim 1. To test the hypothesis that nicotine, via increases in intracellular Ca2+, causes CFTR dephosphorylation and retrograde transport of CFTR to the ER that leads to ASL dehydration.
Aim 2. To assess the impact of nicotine on mucin secretion, mucus/mucin biophysical and barrier properties, including their integrity, polymeric structure, and maturation.
Aim 3. To determine the impact of inhaled nicotine on outcomes of respiratory virus infection in vivo.
Tobacco inhalation is causative in a myriad of diseases including lung cancer, chronic obstructive pulmonary disease and cardiovascular disease. Nicotine is the principle addictive compound in tobacco that keeps people smoking. However, the effects of nicotine on the lung are poorly understood. We shall determine whether nicotine affects the lung's ability to remain hydrated and to keep out viruses.
|Ghosh, Arunava; Coakley, Raymond C; Mascenik, Teresa et al. (2018) Chronic E-Cigarette Exposure Alters the Human Bronchial Epithelial Proteome. Am J Respir Crit Care Med 198:67-76|
|Rowell, Temperance R; Reeber, Steven L; Lee, Shernita L et al. (2017) Flavored e-cigarette liquids reduce proliferation and viability in the CALU3 airway epithelial cell line. Am J Physiol Lung Cell Mol Physiol 313:L52-L66|