Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine
Matthew C. Madison, … , David B. Corry, Farrah Kheradmand
Matthew C. Madison, … , David B. Corry, Farrah Kheradmand
Published April 7, 2020; First published September 4, 2019
Citation Information: J Clin Invest. 2019;129(10):4290-4304. https://doi.org/10.1172/JCI128531.
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Research Article Immunology Inflammation

Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine

Abstract

Electronic nicotine delivery systems (ENDS) or e-cigarettes have emerged as a popular recreational tool among adolescents and adults. Although the use of ENDS is often promoted as a safer alternative to conventional cigarettes, few comprehensive studies have assessed the long-term effects of vaporized nicotine and its associated solvents, propylene glycol (PG) and vegetable glycerin (VG). Here, we show that compared with smoke exposure, mice receiving ENDS vapor for 4 months failed to develop pulmonary inflammation or emphysema. However, ENDS exposure, independent of nicotine, altered lung lipid homeostasis in alveolar macrophages and epithelial cells. Comprehensive lipidomic and structural analyses of the lungs revealed aberrant phospholipids in alveolar macrophages and increased surfactant-associated phospholipids in the airway. In addition to ENDS-induced lipid deposition, chronic ENDS vapor exposure downregulated innate immunity against viral pathogens in resident macrophages. Moreover, independent of nicotine, ENDS-exposed mice infected with influenza demonstrated enhanced lung inflammation and tissue damage. Together, our findings reveal that chronic e-cigarette vapor aberrantly alters the physiology of lung epithelial cells and resident immune cells and promotes poor response to infectious challenge. Notably, alterations in lipid homeostasis and immune impairment are independent of nicotine, thereby warranting more extensive investigations of the vehicle solvents used in e-cigarettes.

Authors

Matthew C. Madison, Cameron T. Landers, Bon-Hee Gu, Cheng-Yen Chang, Hui-Ying Tung, Ran You, Monica J. Hong, Nima Baghaei, Li-Zhen Song, Paul Porter, Nagireddy Putluri, Ramiro Salas, Brian E. Gilbert, Ilya Levental, Matthew J. Campen, David B. Corry, Farrah Kheradmand

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Figure 1

Four-month exposure to ENDS does not induce inflammation in the lung.

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Four-month exposure to ENDS does not induce inflammation in the lung. Mi...
Mice were exposed to room air (Air), cigarette smoke (Smoke), ENDS-vehicle vapor, or ENDS-nicotine vapor for 4 months and the immune profiles of the lung were quantified. (A) Differential BAL cell numbers for macrophages, neutrophils, and lymphocytes in the airway (n = 5 per group). (B) Histological analysis of lung tissue following 4-month exposure. Representative micrographs of H&E staining. Scale bars: 50 μm. (C) MicroCT quantification of total lung volume (n = 5 or 6 per group). (D) BAL cell expression of RNA transcript for matrix metalloproteinase 12 by qPCR (n = 5 or 6 per group). (E) IL-17A, IL-6, and TNF-α concentrations from mouse lung homogenate measured by multiplex assay (n = 4 or 5 per group). (F) Representative and (G) cumulative flow cytometric analysis of live, CD11b+F4/80–Ly6G–CD11c+MHCII+ dendritic cells. Numbers in the upper-right corner indicate percentage positive cells for the markers (n = 5 or 6 per group). (H) Representative and (I) cumulative flow cytometric analysis of live, CD3+CD4+RORγt+IL-17A+ T lymphocytes. Numbers in the upper-right corner indicate percentage positive cells for the markers (n = 5 or 6 per group). Significance was determined by Student’s t test or 1-way ANOVA with Bonferroni’s correction for multiple comparisons. ***P < 0.001, **P < 0.01, *P < 0.05. All data shown are representative of 4 or more independent 4-month experiments with n = 5 or 6.