Elevated Cellular Oxidative Stress in Circulating Immune Cells in Otherwise Healthy Young People Who Use Electronic Cigarettes in a Cross-Sectional Single-Center Study: Implications for Future Cardiovascular Risk

Theodoros Kelesidis, Elizabeth Tran, Sara Arastoo, Karishma Lakhani, Rachel Heymans, Jeffrey Gornbein, Holly R Middlekauff, Theodoros Kelesidis, Elizabeth Tran, Sara Arastoo, Karishma Lakhani, Rachel Heymans, Jeffrey Gornbein, Holly R Middlekauff

Abstract

Background Tobacco cigarettes (TCs) increase oxidative stress and inflammation, both instigators of atherosclerotic cardiac disease. It is unknown if electronic cigarettes (ECs) also increase immune cell oxidative stress. We hypothesized an ordered, "dose-response" relationship, with tobacco-product type as "dose" (lowest in nonsmokers, intermediate in EC vapers, and highest in TC smokers), and the "response" being cellular oxidative stress (COS) in immune cell subtypes, in otherwise, healthy young people. Methods and Results Using flow cytometry and fluorescent probes, COS was determined in immune cell subtypes in 33 otherwise healthy young people: nonsmokers (n=12), EC vapers (n=12), and TC smokers (n=9). Study groups had similar baseline characteristics, including age, sex, race, and education level. A dose-response increase in proinflammatory monocytes and lymphocytes, and their COS content among the 3 study groups was found: lowest in nonsmokers, intermediate in EC vapers, and highest in TC smokers. These findings were most striking in CD14dimCD16+ and CD14++CD16+ proinflammatory monocytes and were reproduced with 2 independent fluorescent probes of COS. Conclusions These findings portend the development of premature cardiovascular disease in otherwise healthy young people who chronically vape ECs. On the other hand, that the COS is lower in EC vapers compared with TC smokers warrants additional investigation to determine if switching to ECs may form part of a harm-reduction strategy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03823885.

Keywords: electronic cigarettes; monocytes; nicotine; reactive oxidative species; tobacco cigarettes.

Conflict of interest statement

None.

Figures

Figure 1. Frequency of immune cell types…
Figure 1. Frequency of immune cell types among smoker groups.
Flow cytometry was used to determine the percentage of different immune cell types in CD45+ immune cells (A through J). The compared groups were nonsmokers (NSs; white), electronic cigarette vapers (EC vapers; light gray), and tobacco cigarette smokers (TC smokers; dark gray). Summary of data (% cellular marker+ of parent population) is shown for CD45+CD15+CD16+CD14−hi‐SSC neutrophils (A), CD45+CD14++CD16− classic monocytes (B), CD45+CD14++CD16+ intermediate monocytes (C), CD45+CD14dimCD16+ nonclassic (patrolling or CD14+CD16++) monocytes (D), CD45+CD14+CD16+ total proinflammatory monocytes (intermediate and nonclassic) (E), CD45+CD3+ T cells (F), CD45+CD3+CD4+ T cells (G), CD45+CD3+CD8+ T cells (H), CD45+CD3−CD56+CD16+ natural killer (NK) cells (I), and CD45+CD19+ B cells (J). Data represent box‐and‐whisker boxes that display the minimum, mean, and maximum (n=9–12 participants per group). The ANOVA statistical test was used to compare 3 groups, and the t test was used to compare 2 groups. The trend P analysis tested the continuum of the difference in measures among groups in an ordered direction (NSs→EC vapers→TC smokers). *P<0.05, **P<0.01, ***P<0.001.
Figure 2. Cellular oxidative stress in CD45…
Figure 2. Cellular oxidative stress in CD45+ immune cells among smoker groups.
Flow cytometry was used to determine total (nuclear and cytoplasmic) and cytoplasmic reactive oxygen species. The compared groups were nonsmokers (NSs; white), electronic cigarette vapers (EC vapers; light gray), and tobacco cigarette smokers (TC smokers; dark gray). Representative data of percentage of immune (CD45+) cells that had positive staining for CELLROX Green among compared groups are shown (A). Summary of data for (A) is shown (B). Representative data of percentage of CD45+ cells that had positive staining for CELLROX Deep Red among compared groups are shown (C). Summary of data for C is shown (D). Representative data of CellROX Green change in mean fluorescence intensity (∆MFI) in CD45+ cells are shown (E). Fluorescence intensity of a positive cell population was compared with a negative cell population (fluorescence minus one negative control for staining) (∆MFI). Summary of data for E is shown (F). Representative data of CellROX Deep Red ∆MFI in CD45+ cells is shown (G). Summary of data for G is shown (H). Data represent box‐and‐whisker boxes that display the minimum, mean, and maximum (n=9–12 participants per group). The ANOVA statistical test was used to compare 3 groups, and the t test was used to compare 2 groups. The trend P analysis tested the continuum of the difference in measures among groups in an ordered direction (NSs→EC vapers→TC smokers). *P<0.05, **P<0.01. SSC indicates side scatter.
Figure 3. Cellular oxidative stress in neutrophils,…
Figure 3. Cellular oxidative stress in neutrophils, natural killer (NK) cells, and B cells among smoker groups.
Flow cytometry was used to determine total (nuclear and cytoplasmic) and cytoplasmic reactive oxygen species. The compared groups were nonsmokers (NSs; white), electronic cigarette vapers (EC vapers; light gray), and tobacco cigarette smokers (TC smokers; dark gray). Summary data of percentage of immune cells that had positive staining for CELLROX Green (A, E, I) and CELLROX Deep Red (C, G, K) and for change in mean fluorescence intensity (∆MFI) CellROX Green (B, F, J) and ∆MFI CellROX Deep Red in cells (D, H, L) among compared groups are shown for CD45+CD15+CD16+CD14−hi‐SSC neutrophils (A through D), CD45+CD3−CD56+CD16+ NK cells (E through H), CD45+CD19+ B cells (I through L). Data represent box‐and‐whisker boxes that display the minimum, mean, and maximum (n=9–12 participants per group). The ANOVA statistical test was used to compare 3 groups, and the t test was used to compare 2 groups. The trend P analysis tested the continuum of the difference in measures among groups in an ordered direction (NSs→EC vapers→TC smokers). *P<0.05, **P<0.01, ***P<0.001.
Figure 4. Cellular oxidative stress in T…
Figure 4. Cellular oxidative stress in T cell subsets among smoker groups.
Flow cytometry was used to determine total (nuclear and cytoplasmic) and cytoplasmic reactive oxygen species. The compared groups were nonsmokers (NSs; white), electronic cigarette vapers (EC vapers; light gray), and tobacco cigarette smokers (TC smokers; dark gray). Summary data of percentage of immune cells that had positive staining for CELLROX Green (A, E, and I) and CELLROX Deep Red (C, G, and K) and for change in mean fluorescence intensity (∆MFI) CellROX Green (B, F, and J) and ∆MFI CellROX Deep Red in cells (D, H, and L) among compared groups are shown for CD45+CD3+ T cells (A through D), CD45+CD3+CD4+ T cells (E through H), and CD45+CD3+CD8+ T cells (I through L). Data represent box‐and‐whisker boxes that display the minimum, mean, and maximum (n=9–12 participants per group). The ANOVA statistical test was used to compare 3 groups, and the t test was used to compare 2 groups. The trend P analysis tested the continuum of the difference in measures among groups in an ordered direction (NSs→EC vapers→TC smokers). *P<0.05, ***P<0.001.
Figure 5. Cellular oxidative stress in monocyte…
Figure 5. Cellular oxidative stress in monocyte subsets among smoker groups.
Flow cytometry was used to determine total (nuclear and cytoplasmic) and cytoplasmic reactive oxygen species. The compared groups were nonsmokers (NSs; white), electronic cigarette vapers (EC vapers; light gray), and tobacco cigarette smokers (TC smokers; dark gray). Summary data of percentage of immune cells that had positive staining for CELLROX Green (A, E, I, and M) and CELLROX Deep Red (C, G, K, and O) and for change in mean fluorescence intensity (∆MFI) CellROX Green (B, F, J, and N) and ∆MFI CellROX Deep Red in cells (D, H, L, and P) among compared groups are shown for CD45+CD15+CD16+CD14−hi‐SSC neutrophils (A through D), CD45+CD3−CD56+CD16+ natural killer cells (E through H), CD45+CD19+ B cells (I through L), and CD45+CD3+ T cells (M through P). Data represent box‐and‐whisker boxes that display the minimum, mean, and maximum (n=9–12 participants per group). The ANOVA statistical test was used to compare 3 groups, and the t test was used to compare 2 groups. The trend P analysis tested the continuum of the difference in measures among groups in an ordered direction (NSs→EC vapers→TC smokers). *P<0.05, **P<0.01, ***P<0.001. MNC indicates monocytes.
Figure 6. Ordered, “dose‐response” relationship in cellular…
Figure 6. Ordered, “dose‐response” relationship in cellular oxidative stress among immune cell types and smoker groups, with tobacco‐product type as “dose.”
EC indicates electronic cigarette; NK, natural killer; ROS, reactive oxygen species; and TC, tobacco cigarette.

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