Abstract
As electronic cigarette (E-cig) use, also known as "vaping", has rapidly increased in popularity, data regarding potential pathologic effects are recently emerging. Recent associations between vaping and lung pathology have led to an increased need to scrutinize E-cigs for adverse health impacts. Our previous work (and others) has associated vaping with Ca2+-dependent cytotoxicity in cultured human airway epithelial cells. Herein, we develop a vaped e-liquid pulmonary exposure mouse model to evaluate vaping effects in vivo. Using this model, we demonstrate lung pathology through the use of preclinical measures, that is, the lung wet: dry ratio and lung histology/H&E staining. Further, we demonstrate that acute vaping increases macrophage chemotaxis, which was ascertained using flow cytometry-based techniques, and inflammatory cytokine production, via Luminex analysis, through a Ca2+-dependent mechanism. This increase in macrophage activation appears to exacerbate pulmonary pathology resulting from microbial infection. Importantly, modulating Ca2+ signaling may present a therapeutic direction for treatment against vaping-associated pulmonary inflammation.
Highlights
Electronic cigarettes, known as electronic cigarette (E-cig), are electronic devices used to heat a liquid to create an aerosol that is inhaled, or “vaped”, by the user
Based upon our previous in vitro studies investigating the role of Ca2+ in e-liquid-induced cytotoxicity and inflammation [12, 14] and our observations of enhanced acute lung pathology after vaped e-liquid pre-exposure and K. pneumoniae infection in comparison to the vaped vehicle followed by K. pneumoniae challenge (Fig 1B and 1C), we further queried the potential of a mechanistic role for Ca2+ signaling in this pathophysiology
To dissect out this mechanism, selective pharmacology was employed to distinguish between the major channels involved in Ca2+ influx due to tobacco/E-cig exposure, that is, store-operated calcium entry (SOCE), non-SOCE and the ER-resident inositol trisphosphate (IP3) receptor, which is the receptor regulating calcium release into the cytosol when activated [33,34,35]
Summary
Electronic cigarettes, known as E-cigs, are electronic devices used to heat a liquid to create an aerosol that is inhaled, or “vaped”, by the user. Studies have tied together an observable cytotoxicity after e-liquid exposure with increases in cytoplasmic calcium (Ca2+) [12,13,14] These earlier studies led us to further investigate the cellular effects of eliquids in vivo. We report on a series of experiments further investigating the pulmonary inflammatory response after exposure to “vaped” e-liquid in an established in vivo model. Using this exposure model, we questioned first whether acute vaping would recapitulate our previously published in vitro findings, and whether vaping might “prime” the immune inflammatory response and result in a worse prognosis after a microbial challenge, that is, vape preexposure would result in a worse outcome compared to no pre-exposure. We treated with well-described Ca2+ receptor antagonists to determine the effects of such compounds, if any, on inflammatory responses
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