Immunomodulation and Inflammation Caused by 4th-generation E-cigarettes in the Setting of Asthma

Va San Diego Healthcare System, San Diego CA

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Linked publications & trials

Abstract

Vaping of nicotine via electronic (e)-cigarettes became popular over the last 10 years and use is higher in Veteran and active-duty military populations. The safety of this behavior is unclear despite some unsubstantiated assurances that vaping might be safer than conventional smoking. Establishing the toxicity of conventional tobacco took several decades of epidemiological studies. However, with the rates of vaping increasing rapidly, experimental evidence is desperately needed to guide public policy before definitive epidemiological data are available. As was the case with tobacco, public health has been threatened by e- cigarette use trends, with minority and vulnerable populations, including Veterans, especially targeted by marketing strategies. We are concerned with the potential toxicity of e-cigarettes on these vulnerable populations, given the absence of reassuring data. Asthma is a highly prevalent disease, with higher rates in Veterans, and (surprisingly) asthmatics often have greater use of tobacco products. The allergic, TH2-high, eosinophilic endo/phenotype of asthma is the most common subtype, representing upwards of 90% of asthma. We hypothesize that TH2-high asthma is susceptible to worsening inflammatory cascades upon exposure to e-cigarette aerosol chemicals. In fact, numerous reports of vaping induced lung disease and exacerbations of existing airways disease have raised the specter of e-cigarettes causing major adverse inflammatory and physiological effects in the lungs over time. By leveraging samples we recently collected from 18-35 year-old e-cigarette vapers of nicotine (n=50), vapers with TH2-high asthma (n=25), non-smoking non-vaping (NSNV) controls (n=25), and NSNV subjects with TH2-high asthma (n=25), the research proposed will obtain cross-sectional data on vaping induced changes in inflammation and immune cell phenotype and function in the setting of TH2-high asthma. These data will help us better understand the risks of e-cigarette use for Veterans with asthma. Specifically, we propose the use of induced sputum, nasal cytology, PAXgene RNA, plasma, and peripheral blood mononuclear cell (PBMC) samples to conduct deep cellular and molecular studies of inflammatory and immune changes associated with e-cigarette use. Data from our 2016-2017 e-cigarette cohort found immunomodulation with primarily down- regulation of inflammatory pathways in the airways of 2nd-3rd gen nicotine e-cigarette users, with concomitant increased systemic inflammation. The interaction of vaping with pre-existing inflammation from TH2-high asthma is the focus of this proposal. We will identify inflammatory pathways modulated by e-cigarette use, with a sub-analysis to assess gender and flavor effects. While defining inflammatory profiles in asthma and non-asthma e-cigarette users, we will also assess for direct toxicity and oxidative stress in the airways. We will take our findings from the human subject samples back to the bench to determine which chemicals within e-cigarette aerosols (vapor) are driving the molecular and cellular changes. We have created a stellar research team that has the expertise to: 1. Utilize existing samples from human subjects (collected 2022-2023) for cutting-edge studies of inflammation and immunity, 2. Study primary human eosinophils from subjects with and without asthma ex vivo to define the effects of vaped e-cigarette chemicals on phenotype and function, and 3. Utilize mouse models of inhalant exposures combined with induction of different phenotypes of allergic inflammatory airways disease (TH2-high eosinophilic and TH2-low neutrophilic mouse models of asthma) to define mechanisms by which chemicals within e-cigarettes promote and modulate inflammation and immune cell function. In this world of high levels of asthma and prevalent use of high-nicotine containing e-cigarettes, it is critical that we define the health effects of these tobacco products when used alone and in the setting of pre-existing inflammatory disease, and define mechanisms by which they cause harm.