Retinal tissue develops an inflammatory reaction to tobacco smoke and electronic cigarette vapor in mice

Abstract

Cigarette smoke has been identified as a major risk factor for the development of age-related macular degeneration (AMD). As an alternative to conventional cigarettes (C-cigarette), electronic cigarettes (E-cigarette) have been globally promoted and are currently widely used. The increasing usage of E-cigarettes raises concerns with regard to short- (2 weeks), medium- (3 months), and long- (8 months) term consequences related to retinal tissue. In this report, a controlled study in mouse models was conducted to probe the comprehensive effects of E-cigarette vapor on retina, retinal pigmented epithelium (RPE), and choroidal tissues by (1) comparing the effects of C-cigarette smoke and E-cigarette vapor on retina separately and (2) determining the effects of E-cigarette vapor on the RPE and analyzing the changes with regard to inflammatory (IL-1β, TNFα, iNOS) and angiogenic (VEGF, PEDF) mediators in retina/RPE/choroid by ELISA assays. The data showed that C-cigarette smoke exposure promoted an inflammatory reaction in the retina in vivo. Mice exposed to E-cigarette (nicotine-free) vapor developed inflammatory and angiogenic reactions more pronounced in RPE and choroid as compared to retinal tissue, while nicotine-containing E-cigarette vapor caused even a more serious reaction. Both inflammatory and pro-angiogenic reactions increased with the extension of exposure time. These results demonstrate that exposure to C-cigarette smoke is harmful to the retina. Likewise, the exposure to E-cigarette vapor (with or without nicotine) increases the occurrence and progression of inflammatory and angiogenic stimuli in the retina, which might also be related to the onset of wet AMD in humans. Key messages C-cigarette smoke exposure promotes an inflammatory reaction in the retina in vivo. Mice exposed to E-cigarette (nicotine-free) vapor develop inflammatory and angiogenic reactions more pronounced in RPE and choroid compared to retinal tissue, while nicotine-containing E-cigarette vapor causes even a more serious reaction. Both inflammatory and pro-angiogenic reactions increase with the extension of E-cigarette vapor exposure time.

Effects of E-Cigarette Refill Liquid Flavorings with and without Nicotine on Human Retinal Pigment Epithelial Cells: A Preliminary Study

“…Our results of declines in mitochondrial membrane potential induced by the vehicle (PG/VG) alone indicate that the vehicle in EC can in itself impair functions. A previous report where mice were exposed to EC vapors showed damage to retinal microvasculature by the PG vehicle [ 28 ] while another study postulated that the vapors generated from PG produced formaldehyde on heating which led to ischemia and cellular damage in retinal vessels [ 27 ]. Although we did not observe any significant effect of flavors per se on mitochondrial membrane potential, the possibility that these flavors might contribute to oxidative stress by inducing the production of reactive oxygen species (ROS) cannot be ruled out, since it has been reported previously that flavors in EC induced the generation of hydroxyl radicals and ROS [ 51 , 52 ].…”

“…To the best of our knowledge, there is only one recent in vivo study where the authors evaluated the effects of chronic e-cigarette vapor on mouse RPE in addition to the choroid and retina, although they did not test any flavor. Short-term e-cigarette exposures can provide initial evidence of biochemical changes in cells and can help narrow down the most important flavored e-liquids; long-term in vivo studies can then be conducted in the future to test these selected flavored e-liquids in models of chronic smoke exposure, similar to the study in the mouse model [ 28 ]. We did not evaluate the effects of the panel of e-cigarette liquids on RPE cytokine/chemokine in this study since that was not the primary focus of the study.…”

“…We did not evaluate the effects of the panel of e-cigarette liquids on RPE cytokine/chemokine in this study since that was not the primary focus of the study. In addition, Wang et al [ 28 ] showed that exposure to nicotine-free or nicotine-containing unflavored e-cigarette vapors over a short-term duration of 2 weeks did not cause any significant alterations on proinflammatory cytokine levels (although the anti-angiogenic pathway was activated) in mouse retinal epithelium. It was only after a long-term exposure of 3 months, that the authors reported significant upregulation in the protein levels of cytokines VEGF, IL-1β, and iNOS.…”

“…Future studies to test EC vapor condensates and comparison with cigarette smoke extract will also be helpful to ascertain if ECs are more harmful. Currently, only one in vivo study [ 28 ] exists where the authors demonstrated that whole body exposure of mice to cigarette or unflavored e-cigarette over 3 months caused similar adverse outcomes of upregulation in inflammatory markers in the retinal tissue. Moreover, other studies that have compared cigarette smoke and e-cigarette exposure have shown that toxicity induced by e-cigarette aerosols in bronchial epithelial cells (obtained from patients with COPD) was comparable to that of cigarette smoke [ 60 ].…”

“…In one study, the authors demonstrated that EC use in healthy men led to decreased vascular density with development of hypoxia in retinal tissue [ 27 ]. In another study, whole-body exposure of mice to vapors from unflavored nicotine-free and unflavored nicotine-rich EC showed damage to retinal microvasculature; the presence of nicotine led to further enhanced secretion of inflammatory mediators and angiogenic factors exacerbating the damage [ 28 ]. To the best of our knowledge, there is no report on the effects of EC liquid flavorings on retinal exposure to date.…”