<p>The Particle in Exhaled Air (PExA) method provides a non-invasive way to evaluate how electronic (e)-cigarette aerosols affect the small airways by providing a sample of their lining fluid. This study explored for the first time the changes in the lipid profiles of airway lining fluid and their links to systemic inflammatory marker IL-13-producing T cells in blood, local airway type Ⅱ inflammatory marker FeNO, and local innate immune marker TLR2 in sputum among e-cigarette users, cigarette smokers, and non-smokers.</p><p>PEx samples were collected on a single occasion from 24 non-smokers, 21 cigarette smokers, and 17 e-cigarette users aged 20 to 65 years. Participants completed a questionnaire including information on cigarette and e-cigarette use. All participants had normal lung function (FEV₁/VC ≥ 0.7) and no history of allergy or lung diseases. Statistical significances were tested by the Kruskal-Wallis test followed by the Mann-Whitney test as post-hoc, linear regression, and OPLS-DA analysis.</p><p>A total of 86 lipid species across 9 lipid classes were identified in the analysis. Significant differences in both phospholipid classes and individual lipid species were found among e-cigarette users, cigarette smokers, and non-smokers, with the most pronounced differences between e-cigarette users and non-smokers. Notably, the percentages of lysophosphatidylcholine (LPC), sphingomyelin (SM), and phosphatidylethanolamine (PE) lipid classes were higher in e-cigarette users compared to non-smokers. Additionally, a strong association was identified between IL-13-producing T cells and lipid profiles in e-cigarette users compared to non-smokers.</p><p>The observed changes in lipid profiles among e-cigarette users may indicate disruptions in lipid homeostasis linked to chronic inflammatory lung diseases. This underscores the need for further research on the long-term effects of e-cigarette use, as the precise implications remain unclear.</p>