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.
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.
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