Using PET to Measure Pulmonary Oxidative Stress in E-cigarette Users

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Worldwide, more than 3.5 million people die annually from smoking-related lung diseases. Although public awareness regarding smoking-related risks has increased and tobacco smoking has declined in the United States, the use of Electronic Nicotine Delivery Systems, or ENDS (e.g., e-cigarettes, vape pens), has dramatically increased, particularly among youth and young adults. The increased popularity of ENDS is due in part to targeted marketing efforts asserting that these products represent a “safer alternative” to traditional cigarettes. To date, however, there is a paucity of human data on the potential toxicity of ENDS use, particularly relative to that of cigarette smoke. Inducible nitric oxide synthase (iNOS) is an enzyme that is constitutively expressed in lung epithelium and is specific for inflammation, a common pathway for many types of lung disease. We propose to measure lung inflammation using Positron Emission Tomography (PET) imaging with [18F]-6- (1/2)(2-fluoro-propyl)-4-methylpyridin-2-amine ([18F]NOS), an exciting new PET radiotracer that targets the inducible isoform of nitric oxide synthase. The goal of the proposed study is to leverage our experience with this novel imaging technique to compare, for the first time, lung inflammation in ENDS users with cigarette smokers and nonsmokers. Specifically, we will quantify, localize, and compare, for the first time, lung inflammation in ENDS users with cigarette smokers and nonsmokers using PET lung imaging with [18F]NOS (Aim 1) and examine and compare biomarkers of airway (fractional exhaled nitric oxide (FeNO)) and lung inflammation (i.e., pro- inflammatory cytokines (TNF-α, IL-1β, IL-8)) and lung function (as measured by forced expiratory volume (FEV) and forced vital capacity (FVC) using spirometry) (Aim 2). To accomplish these goals, 60 subjects [3 groups of 20: ENDS users, traditional cigarette smokers, and nonsmoking controls] will be carefully screened and smoking status will be biochemically verified. Subjects will complete self-report measures, undergo a one-hour [18F]NOS PET/CT (computed tomography) scan of the chest, provide a breath and blood sample for measurement of biomarkers of airway and lung inflammation, and complete lung function tests using spirometry. The proposed study would be the first use of [18F]NOS PET lung imaging to localize and quantify the extent of lung inflammation, examine biomarkers of airway and lung inflammation, and lung function due to ENDS use and cigarette smoking. By measuring specific inflammatory effects of ENDS use on lung tissue, our proposal directly supports the FDA's goal of developing ENDS product standards to protect public health.