UC Davis

Electronic cigarettes (E-cigarettes) were originally designed in 2003 as smoking cessation devices intended to deliver nicotine without the need for combustion. E-cigarettes, also known as electronic nicotine delivery systems (ENDS), have since gained widespread popularity across the globe among both current and former tobacco smokers, and those who have never smoked before. Concerningly, e-cigarette popularity has also spread to adolescents with recent estimates that over 2 million middle and high school students currently use e-cigarettes. The efficacy of e-cigarettes as smoking cessation aids is highly contested, and the FDA has not yet approved any e-cigarette device for this purpose. There exists an ever-expanding body of knowledge regarding the potential health hazards of continued e-cigarette use. E-cigarettes, which exist in many forms, or ‘generations’, that vary in design and efficiency at aerosolizing nicotine, share three core elements: a power source (battery), heating element (coil or atomizer) and a reservoir containing e-liquid (composed of the humectants propylene glycol (PG) and vegetable glycerin (VG), nicotine and flavoring chemicals). Aerosols, generated by heating of the coil to aerosolize e-liquid, are known to contain numerous toxic chemicals that are also found in cigarette smoke. In particular, research has consistently shown e-cigarette aerosols contain carbonyls, metals, free radicals, and nicotine by-products. Popular e-cigarette devices, called third-generation devices, allow users to adjust device settings like coil temperature and power, and can be used with low resistance “sub-ohm” coils made from numerous different metals and in many different coil configurations. Popular fourth-generation devices are less customizable but use highly bio-active nicotine salts, which increase nicotine delivery to users. E-cigarette research is challenging and complex due mostly to the numerous model types of e-cigarette devices available on the market, which evolved from first- to now fourth- generation, with over 2,800 different models from 466 identified brands, and to the selection of more than 16,000 distinct e-liquid flavors. In addition, each combination of e-liquid variables (humectants, flavors, nicotine concentration) and device operating conditions (wattage and temperature settings) is unique and produces a specific toxicity profile. In humans, e-cigarette use has been shown to cause acute adverse respiratory, cardiovascular, digestive, and neurologic health effects, among others. Evidence has also emerged that e-cigarette users can experience immunological disturbances leaving them at increased risk for respiratory infections, such as COVID-19 or influenza. Studies in vitro and in vivo in rodents have implicated e-cigarettes in disruption of pulmonary immune homeostasis leading to aberrant cytokine and chemokine production and altered immune cell functions. However, the exact mechanisms of action and the long-term health consequences of these changes are still largely unknown. Notably, vulnerable populations like fetuses, infants, children, pregnant women, and older adults may be uniquely vulnerable to immune related health risks associated with e-cigarette use. Herein, we review the effects of e-cigarettes use on both maternal and fetal health outcomes, as well as consequences of early-life e-cigarette exposures in infants and children. We then investigate the effects of increased coil temperature on the chemical composition of aerosol from a third-generation e-cigarette device, and on pulmonary inflammation in murine lungs. We find that increased coil temperature does not significantly increase carbonyl compound concentrations, but that exposures to aerosols generated at higher temperatures can more significantly dampen pulmonary cytokine production and macrophage recruitment to lungs. We then investigate progressive exposure to e-cigarette aerosols and compare this to traditional cigarette smoke exposure in mice. We find that progressive e-cigarette exposure induces a unique, acute inflammatory response compared to cigarette exposure, characterized by transient macrophage infiltration to lungs. We also find that progressive e-cigarette exposure reduces cytokine gene expression indicating a potentially immunosuppressive effect. Lastly, we investigate the effects of e-cigarettes on the pulmonary immune system and host responses to influenza A viral infection in both young and aged mice. We find that viral titers are reduced, viral clearance is impaired, and mortality from infection is decreased in e-cigarette exposed mice. We find that e-cigarette exposure caused significant shifts throughout infection in both innate and adaptive immune cell populations and cytokine profiles which persisted after resolution of infection, underscoring the potential health risks associated with e-cigarette use. Of note, during early infection, Natural Killer (NK) cell populations were significantly increased in both mouse strains and both ages, indicating a consistent phenotype which to our knowledge has not been reported previously. The studies contained herein further the current understanding of the impacts of e-cigarettes on pulmonary immune homeostasis and underscore the need for continued regulation of e-cigarette sales to minimize negative public health outcomes.