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. 2021 Dec 1;321(6):L1134-L1146.
doi: 10.1152/ajplung.00363.2021. Epub 2021 Oct 27.

Inflammatory phenotype modulation in the respiratory tract and systemic circulation of e-cigarette users: a pilot study

Ibrahim M Sayed  1 , Jorge A Masso-Silva  2   3 , Ankita Mittal  3 , Arjun Patel  2 , Erica Lin  2   3 , Alex Moshensky  2   3 , John Shin  2   3 , Christine M Bojanowski  4 , Soumita Das  1 , Praveen Akuthota  3 , Laura E Crotty Alexander  2   3
Affiliations

Inflammatory phenotype modulation in the respiratory tract and systemic circulation of e-cigarette users: a pilot study

Ibrahim M Sayed et al. Am J Physiol Lung Cell Mol Physiol. .

Abstract

Over 40 million people use e-cigarettes worldwide, but the impact of chronic e-cigarette use on health has not been adequately defined. In particular, effects of e-cigarette aerosol inhalation on inflammation and host defenses across the body are not fully understood. We conducted a longitudinal cohort pilot study to explore changes in the inflammatory state and monocyte function of e-cigarette users (n = 20) versus healthy controls (n = 13) and to evaluate effects of e-cigarette use reduction on the same. Saliva, sputum, and blood were obtained from e-cigarette users at baseline and after a 2-wk intervention of decreased e-cigarette use. Overall, across 38 proteins quantified by multiplex, airway samples from e-cigarette users tended to have decreased levels of immunomodulatory proteins relative to healthy controls, whereas levels of cytokines, chemokines, and growth factors in the circulation tended to be elevated. Specifically, e-cigarette users had lower levels of IL-1 receptor antagonist (IL-1Ra) in saliva (P < 0.0001), with higher IL-1Ra and growth-regulated oncogene (GRO) levels in sputum (P < 0.01 and P < 0.05, respectively), and higher levels of both TNFβ (P < 0.0001) and VEGF (P < 0.0001) in plasma. Circulating monocytes from e-cigarette users had alterations in their inflammatory phenotype in response to reduced e-cigarette use, with blunted IL-8 and IL-6 release upon challenge with bacterial lipopolysaccharide (P < 0.001 and P < 0.05, respectively), suggesting a decreased ability to appropriately respond to bacterial infection. Based on these findings, chronic inhalation of e-cigarette aerosols alters the inflammatory state of the airways and systemic circulation, raising concern for the development of both inflammatory and infectious diseases in chronic users of e-cigarettes.

Keywords: cytokine; e-cigarette; host defense; inflammation; monocyte.

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Conflict of interest statement

P.A. has received research funding from AstraZeneca, GlaxoSmithKline, and Regeneron and has received consultancy fees from AstraZeneca and GlaxoSmithKline. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

Figures

Figure 1.
Figure 1.
E-cigarette use associated alterations in immunomodulatory protein levels in saliva, sputum, and plasma. A: inflammatory markers were assessed in the saliva of nonsmoking nonvaping healthy controls (n = 11; blue circles) and e-cigarette users at baseline (n = 17; solid red squares), with lower levels of IL-1RA identified in the oral airways of e-cigarette users. B: IL-1RA remained low in e-cigarette users after 2 wk of reduced e-cigarette usage (n = 14; hollow red squares). C: sputum demonstrated reductions in both GRO and IL-1RA in the lower airways of e-cigarette users vs. healthy controls. D: GRO and IL-1RA remained low in lower airway samples after 2 wk of reduced e-cigarette usage. E: plasma samples demonstrated elevations in TNFβ and VEGF in the circulation of e-cigarette users vs. controls. F: after 2 wk of reduced e-cigarette use, plasma levels of TNFβ and VEGF were persistently elevated. Data are represented as individual data points with the geometric mean. Statistical analysis was conducted with two-way ANOVA with correction for multiple comparisons by controlling the false discovery rate, using the two-stage step-up method of Benjamini, Krieger, and Yekutieli. *P < 0.05, **P < 0.01, and ****P < 0.0001.
Figure 2.
Figure 2.
Exploratory assessment of inflammatory modulatory proteins, chemokines, and growth factors in saliva samples. Inflammatory markers were assessed in the saliva of nonsmoking healthy controls (black), e-cigarette users at baseline (red) and after 2 wk of reduced e-cigarette usage (blue). Only the analytes with statistically significant differences by Student’s t test (without controlling for multiple comparisons) were included in this figure and are further separated into cytokines (A–N), chemokines (O–R), and growth factors (S–T). Paired lines between e-cigarette and reduced dose represent the change in the levels in the same individual after reducing the e-cigarette dose. Error bars represent the means ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, as determined by Student’s t test.
Figure 3.
Figure 3.
Exploratory assessment of inflammatory modulatory proteins, chemokines, and growth factors in sputum samples. Inflammatory markers were assessed in the sputum of nonsmoking healthy controls (black), e-cigarette users at baseline (red) and after 2 wk of reduced e-cigarette usage (blue). Only the analytes with statistically significant differences by Student’s t test (without controlling for multiple comparisons) were included in this figure and are further separated into cytokines (A–J), chemokines (K–L), and growth factors (M–O). Paired lines between e-cigarette and reduced dose represent the change in the levels in the same individual after reducing the e-cigarette dose. Error bars represent the means ± SD. *P < 0.05, and **P < 0.01, as determined by Student’s t test.
Figure 4.
Figure 4.
Exploratory assessment of inflammatory modulatory proteins, chemokines, and growth factors in plasma samples. Inflammatory markers were assessed from the plasma in nonsmoking healthy controls (black), e-cigarette users at baseline (red) and after 2 wk of reduced e-cigarette usage (blue). Only the analytes with statistically significant differences by Student’s t test (without controlling for multiple comparisons) were included in this figure and are further separated into cytokines (A–E), chemokines (F–I), and growth factors (J–L). Paired lines between e-cigarette and reduced dose represent the change in the levels in the same individual after reducing the e-cigarette dose. Error bars represent the means ± SD. *P < 0.05, **P < 0.01, and ****P < 0.0001, as determined by Student’s t test.
Figure 5.
Figure 5.
Reductions in sputum and plasma immunomodulatory proteins in response to short-term reduction in e-cigarette use. A: IL-1RA in saliva modestly increased after 2 wk reduction in vaping. B: in sputum, four proteins had diminished levels in the setting of short-term reduced vaping, GRO, IL-1RA, IL-8, and IP-10. C: plasma samples demonstrated reduced levels of TNFβ and VEGF in the circulation of e-cigarette users in response to 2 wk of reduced e-cigarette use. Individual data points are shown with the mean and 95% CI. Statistical analysis was conducted with two-way ANOVA with correction for multiple comparisons by controlling the false discovery rate, using the two-stage step-up method of Benjamini, Krieger, and Yekutieli. *P = 0.02, #P = 0.03, **P < 0.01, and ****P < 0.0001. CI, confidence interval.
Figure 6.
Figure 6.
E-cigarette alters the inflammatory response of circulating human monocytes. Inflammatory markers TNFα (A–C), IL-6 (D–F), and IL-8 (G–I) were obtained from circulating monocytes in nonsmoking nonvaping healthy controls (black) and from e-cigarette users at baseline (red) and after 2 wk of reduced e-cigarette usage (blue). This figure is further separated into cytokines secreted under unstimulated conditions (A, D, and G) and LPS-stimulated conditions (B, E, and H). Normalized TNFα (C), IL-6 (F), and IL-8 (I) were calculated by dividing cytokine levels from LPS-stimulated monocytes by cytokine levels from nonstimulated monocytes from each subject. Paired lines between e-cigarette and reduced use represent paired changes in cytokine levels from the same subject in the setting of reducing use of e-cigarettes. Error bars represent the means ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, as determined by Student’s t test. LPS, lipopolysaccharide.
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