to the editor: We appreciate the interest and discussion by Drs. Emma, Caruso, and Polosa related to our manuscript (1). We very much agree with the authors that definition and selection criteria of participants are important aspects to consider to avoid bias, which is why we carefully documented individual self-reported cigarette smoking and e-cigarette use and assessed biochemical markers of exposure to assure exclusion of dual users (see Supplemental Table S1 in Ref. 2). We would also like to point out that not every e-cigarette user included in our study was an ex-smoker. As described in our article, 3 of the 12 e-cigarette users were never smokers (see materials and methods section). Unfortunately, these numbers did not allow us to conduct a direct comparison between e-cigarette users who are former smokers and never smokers, which we discussed thoroughly in the article. As indicated by the authors, this is an important comparison, which is the focus of our ongoing studies. We also agree with the authors that exposure to cigarette smoke causes epigenetic modifications resulting in gene expression changes even after smoking cessation. Indeed, in our discussion we cite previous studies documenting irreversible gene expression changes in former smokers (4). In addition, our own previous studies document epigenetic changes in nasal epithelial cells from smokers (3), which was also included in the discussion. However, while previous smoking history likely modifies gene expression changes in nasal epithelial cells, we have no reason to believe that the previous smoking history was significantly greater in our e-cigarette user group compared with the cigarette smoker group, thus accounting for the vastly different immune gene expression changes caused in the two groups, as suggested by the authors. The average age in our comparison groups was relatively young (smokers = 30.71 ± 5.64 years; e-cigarette users = 26.33 ± 5.57) with no signs of any smoking-related diseases or other pulmonary symptoms (see materials and methods). Considering that 3 of the 12 e-cigarette users included in this study were never smokers (i.e., pack-years = 0) may even suggest that the prior cigarette smoking history was lower in e-cigarette users, thus making the argument posed by the authors that the “large number of genes in the vapers group is obviously related to their previous smoking history” unsubstantiated. Lastly, we do agree with the authors that a longitudinal study would be able to better establish causation of e-cigarette-induced effects on gene expression changes in humans. This is indeed the emphasis of ongoing studies in our laboratory, allowing us to further assess e-cigarette use-dependent immune gene expression changes in the respiratory mucosa.
No conflicts of interest, financial or otherwise, are declared by the author(s).
I.J. drafted manuscript; I.J. edited and revised manuscript; I.J. approved final version of manuscript.
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