Impact of Vaping and Multi-inhalant Use on Gene Expression and Inflammatory Protein Profiles in the Airways and Circulating Immune Cells

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Abstract Rationale: The rapid evolution of both nicotine and THC vaping devices in the past decade, and increased use by youth, has raised questions about potential health effects. Likely due to conflicting messaging on e-cigarettes being safer than smoking, large subsets of vapers use e-cigarettes in conjunction with traditional combustible tobacco or cannabis. Little is known about the complex interplay between vaping, smoking, and the immune system. Here we studied different inhalant groups over time to elucidate physiological and immunological consequences of chronic inhalant use. Method: A longitudinal study of human subjects ages 18-35 was conducted. Subjects were recruited, enrolled and underwent informed consent before being categorized into inhalant groups based on self-report: never-vaper/never-smoker, nicotine vaper, THC vaper, both nicotine and THC vaper (dual users), as well as subgroups based on current conventional tobacco and cannabis smoking. Data was collected from 23 controls, 39 nicotine vapers (8 who also smoke tobacco and/or cannabis), 17 dual vapers (13 who also smoke tobacco and/or cannabis), and 9 THC vapers (8 who also smoke cannabis and/or tobacco.RNAseq was conducted on: 1. PaxGene tubes, 2. Peripheral blood mononuclear cells (PBMCs), and 3. Nasal cytology. Inflammatory protein multiplex was conducted on serum, and mitochondrial DNA was quantified by droplet digital PCR in plasma of e-cigarette vapers as well. Results: Nine genes were significantly upregulated in the nasal epithelium of E-cigarette vapers, and 1 gene was downregulated, relative to controls (see volcano plot in Figure 1). Transcriptomic analyses of PBMCs and blood (PAXgene) also showed numerous changes in genes relating to inflammation and immunity, consistent with immunomodulation caused by inhalation of aerosols with and without concomitant smoke inhalation. Plasma mitochondrial DNA levels were increased in a subset of nicotine vapers relative to controls, while IL-10 was increased in the circulation of cannabis users. Conclusion: Chronic e-cigarette vaping alters gene expression in upper airways and in circulating leukocytes – both PBMCs and neutrophils. The elevation in plasma IL-10 in cannabis users suggests activation of inflammatory responses, or even lung damage, leading to secretion of IL-10 as a feedback mechanism to prevent further damage. Elevations in plasma IL-10 are seen in ARDS, septic shock and hyperinflammatory states in general, and IL-10 has been implicated in causing immunosuppression and thus increasing mortality. Our current cohort is undergoing their 2nd and 3rd annual visits, which should yield further insight into chronic effects of vaping and multi-inhalant use on inflammation and immunity.

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