Overall, these findings suggest that components other than nicotine may contribute to the observed neuroinflammatory changes. Further research is needed to better understand how specific, non-nicotine JUUL components contribute to inflammatory and neuronal effects. As the entry point to the body for inhalants, the lungs get a high level of exposure to the chemicals within e-cigarette aerosols (Grana et al., 2014). Because the size of e-cigarette aerosols, they reach deep into the lungs, even further than conventional tobacco smoke (Manigrasso et al., 2015). While it may take decades for us to fully understand the pathologic effects of e-cigarette aerosols on the lungs, animal models can provide some insight as to what physiologic, inflammatory, and even carcinogenic effects may occur.

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In addition to your lungs, nicotine and other substances in e-liquid can hurt your heart and brain. We know nicotine can hurt brain development, raise your blood pressure and narrow your arteries. We have altered the wording throughout the manuscript to clarify that the 3-month duration is equivalent to 10 to 20 years of inhalant use versus 40 to 50 years for a 6 to 12 month model. We have also removed many instances of the descriptive terms acute, sub-acute and chronic across the manuscript, as focused on using the absolute duration of exposure instead, to avoid accidental extrapolation to longer exposures. Because we utilized cellular and molecular based assays, we were not relying on identifying organ level pathology such as fibrosis, emphysema, and organ dysfunction, all of which would require longer exposures. In the introduction and Discussion sections, the authors should consider including all in vitro and in vivo studies that have been conducted on JUUL aerosols, since there are very few of those already published articles.

Harm reduction

Hon quit smoking after his father, also a heavy smoker, died of lung cancer. In 2001, he thought of using a high frequency, piezoelectric ultrasound-emitting element to vaporize a pressurized jet of liquid containing nicotine. Hon said that using resistance heating obtained better results and the difficulty was to scale down the device to a small enough size.

This work, and thus this manuscript, was designed to highlight changes at the gene expression level, to demonstrate that e-cigarette use is not benign and does have broad-reaching effects on gene expression. We agree that more work is needed to fully define the impact of e-cigarette use at the protein, cellular, and organ level, but the majority of that work is beyond the scope of this manuscript. These new data support the hypothesis that e-cigarette aerosol inhalation fundamentally alters the lung, which raises the specter of downstream health effects. Of note, in the original submission, we included protein quantification data for both the brain and the lung . Methods, results, and discussion related to the RNAseq results have been added to the manuscript.

The vape pens and cig-a-likes were the first e-cigarettes studied from 2007 to 2014, whereas the box Mods became highly popular and research on these devices began around 2015. Pod devices, including the JUUL, were invented in 2016 and rapidly dominated the market by 2017–2020 . These pod-based devices produce aerosols with a different chemical composition than prior devices, including often significant higher concentrations of nicotine than Mod devices. Studies of JUUL to date have been predominantly subacute and acute exposures with a focus on in vitro and in vivo experiments.

Thank you for submitting your article “Effect of chronic JUUL aerosol inhalation on inflammatory states of the brain, lung, heart and colon” for consideration by eLife. Your article has been reviewed by 3 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Paul Noble as the Senior Editor. พอต , heart rate variability and blood pressure measurements were taken after the last exposure to JUUL aerosol or Air at 1 and 3 months, via the Emka non-invasive ECG Tunnels and the CODA non-invasive blood pressure system. Prior to data collection, mice were acclimated for 20 min per day for the last 3 days in the ECG and blood pressure systems. Heart rate variability was determined through time-domain measurements, specifically SDNN and RMSSD.