Project Summary Over the past ten years, electronic cigarettes (e-cigarettes) have been commercialized as a “less harmful” alternative to traditional cigarettes. Preclinical models show that e-cigarettes cause pulmonary epithelial, endothelial, and vascular dysfunction similar to human COPD. E-cigarette use has also been associated with cardiac and pulmonary diseases, including severe respiratory failure. However, we still do not clearly understand how e-cigarette uses impacts lung health in the early days of use. Therefore, there is an urgent need to establish the health impact of e-cigarettes on human lungs. Conventional diagnostic tools such as pulmonary function tests (PFT) and multi-detector computed tomography (MDCT) are limited in detecting subtle but potentially significant early pathologies from e-cigarette use. To address this shortcoming, we propose to use 3D hyperpolarized xenon-129 MRI (HXeMRI) as a new imaging biomarker. Our group has optimized the HXeMRI technique to quantify the regional physiology of pulmonary microcompartments (airway, interstitial tissues, and capillary vasculature) with high resolution and sensitivity. Our HXeMRI pilot study demonstrated that healthy young e-cigarette users with normal PFT had dysregulated gas exchange in the interstitial tissue and pulmonary capillary compartments compared to age-matched controls. Based on these preliminary data, we hypothesize that quantitative HXeMRI signatures can detect clinically relevant early physiologic changes in the lungs of healthy young e-cigarette users. We speculate that a cardiopulmonary exercise test (CPET) will exacerbate these dysregulated lung functions and limit healthy young e-cigarette users’ exercise capacity by reducing their oxygen uptake. Therefore, we hypothesize that the CPET, a clinical diagnostic standard, will corroborate HXeMRI signatures. To the best of our knowledge, this is the first time any non-invasive technique has revealed dysfunctional gas exchange capacity in healthy young e-cigarette users with normal PFT. Our two aims are: (1). Aim 1: Determine the impact of e-cigarette use on pulmonary gas exchange capacity in interstitial tissues and capillaries using HXeMRI, and corroborate the HXeMRI signatures with the CPET for 40 young adults with e- cigarette use at an initial visit (V1) and a follow-up visit 12-months later (V2), compared to 40 age-matched healthy control subjects without e-cigarette use as controls; and (2). Aim 2: Determine the acute effects of e- cigarettes on pulmonary gas exchange capacity in interstitial tissues and capillaries among the e-cigarette users from Aim 1 by HXeMRI at baseline and after being perturbed by a dose of e-cigarettes during the V1 and V2 evaluations. The result of our proposal is anticipated to yield a comprehensive understanding of the health impact of e-cigarette use and bring forth gas exchange signatures of HXeMRI as a new diagnostic tool to assess these patients.