Nicotine is a major component of nicotine delivery systems [Electronic Nicotine Delivery Systems (ENDS)] i.e. electronic cigarettes (e-cigs). Nicotine is known to have the addictive properties, and a knowledge gap exists on how inhaled nicotine affects the pulmonary system. Our supporting data show that ENDS nicotine aerosol delivery and exposure cause oxidative stress and inflammatory responses in human lung epithelial cells, fibroblasts, and in mouse lungs. Currently, no information is available on the biological effects of e-cig containing inhaled nicotine in humans and in mouse models. Inhaled nicotine may contribute to the pathogenesis of lung diseases in particular via lung inflammation, injurious, and dysregulated repair responses. We hypothesize that e-cig nicotine influences toxicity as evidenced by oxidative and inflammatory responses in humans and in mouse models, leading to dysregulated repair and emphysematous responses.
Three specific aims are proposed to test this hypothesis:
Aim 1 : Inhaled nicotine induces lung and systemic inflammatory mediators in human subjects Determine the impact of inhaled nicotine in users and non-users of e-cigarettes. This will be accomplished by monitoring biomarkers of exposure (inflammatory, exosomes and lipid mediators by lipidomics) in human biofluids (saliva, Exhaled Breath Condensate, plasma, and urine) along with clinical outcomes (lung function tests) in a prospective cohort study (baseline and follow-up). Along with human studies, we plan to conduct mechanistic studies in vivo and in vitro.
Aim 2 : Inhaled nicotine induces lung inflammatory and dysregulated repair responses via its receptor Here, we will use a mouse preclinical model for mechanistic studies. We will determine if e-cigarettes containing low and high nicotine concentrations have differential pro-inflammatory and abnormal repair effects in vivo via the ?7 nicotinic acetylcholine receptor (?7nAChR) dependent mechanism.
Aim 3 : Mechanisms whereby nicotine aerosol induces inflammatory and dysregulated cellular repair responses Determine inflammatory and dysregulated cellular repair responses to e-cigarette nicotine vapor in human lung epithelial cells and fibroblasts using the state-of-the-art reporter models (NF-?B luciferase) as well as a 3-D cell culture model. This will determine how nicotine affects cellular processes, such as early cellular senescence and myofibroblast differentiation, as well as lipogenic and myogenic pathways in healing/repair process. The outcomes of this study will provide an understanding of the clinical impact and mechanisms of inflammatory, senescence, and dysregulated repair responses following nicotine exposure in human subjects and, in primary lung cells in vitro and mouse model in vivo.

Public Health Relevance

Electronic cigarettes are being increasingly used. A major health concern is that nicotine present in these inhaled aerosols/vapors may cause lung damage. We propose to examine the clinical impact of nicotine on lung function in humans and mice, and to determine the oxidative, inflammatory, dysregulated repair/pro- fibrogenic responses incited by e-cigarette nicotine smoking (vaping). These results will provide insight into the mechanisms of toxicity and clinical outcomes of inhaled nicotine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135613-04
Application #
9856316
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Postow, Lisa
Project Start
2017-01-16
Project End
2021-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Javed, F; Kellesarian, S V; Sundar, I K et al. (2017) Recent updates on electronic cigarette aerosol and inhaled nicotine effects on periodontal and pulmonary tissues. Oral Dis 23:1052-1057
Javed, Fawad; ALHarthi, Shatha Subhi; BinShabaib, Munerah Saleh et al. (2017) Toxicological impact of waterpipe smoking and flavorings in the oral cavity and respiratory system. Inhal Toxicol 29:389-396
Muthumalage, Thivanka; Prinz, Melanie; Ansah, Kwadwo O et al. (2017) Inflammatory and Oxidative Responses Induced by Exposure to Commonly Used e-Cigarette Flavoring Chemicals and Flavored e-Liquids without Nicotine. Front Physiol 8:1130
Sundar, Isaac K; Rashid, Kahkashan; Sellix, Michael T et al. (2017) The nuclear receptor and clock gene REV-ERB? regulates cigarette smoke-induced lung inflammation. Biochem Biophys Res Commun 493:1390-1395
Lei, Wei; Lerner, Chad; Sundar, Isaac K et al. (2017) Myofibroblast differentiation and its functional properties are inhibited by nicotine and e-cigarette via mitochondrial OXPHOS complex III. Sci Rep 7:43213
Gerloff, Janice; Sundar, Isaac K; Freter, Robert et al. (2017) Inflammatory Response and Barrier Dysfunction by Different e-Cigarette Flavoring Chemicals Identified by Gas Chromatography-Mass Spectrometry in e-Liquids and e-Vapors on Human Lung Epithelial Cells and Fibroblasts. Appl In Vitro Toxicol 3:28-40