Vaping α-T-acetate Generates a Novel Toxic Compound that Induces Fever and Lung Inflammation - Vaping has become popular among teens and young adults. It has been reported that an acetate conjugate of vitamin E, α-tocopherol-acetate (α-T-acetate), has been added to some base e-liquids for vaping. α-T-acetate in e-liquids is linked to E-cigarette, or vaping associated lung injury (EVALI) and deaths. There were 2,807 illness and 68 deaths (by October 2020) associated with vaping. α-T-acetate is in the bronchoalveolar lavage of EVALI patients, and vaping α-T-acetate and other acetate conjugates is still occurring. Patients with EVALI have lung symptoms of cough, shortness of breath, or chest pain, as well as fever, nausea, vomiting, diarrhea, fatigue or weight loss. EVALI patients have elevated systemic inflammatory mediators and lung remodeling. The CDC suggested that the lipid α-T-acetate not be added to vaping products until mechanistic studies are done. We propose novel mechanisms for manifestations of EVALI from vaping α-T-acetate. Our novel preliminary data indicate that a novel high molecular weight compound is generated from vaping α-T-acetate and that this compound would not be detected in the LC-MS approaches in previous reports on vaped compounds. The novel compound was toxic to epithelial cells, induced eosinophilia, fever and overt lung remodeling in mice, but did not lipid-load lung macrophages. In contrast, non-vaped α-T-acetate in base e-liquids do lipid-load lung macrophages but this does not induce fever. Although, we show that a high molecular weight toxic compound is generated and we have separated the compound, the structure of the toxic compound, and the mechanisms for induction of fever, lung damage and lung inflammation by this novel compound are not known. Our novel concept is that a novel high molecular weight compound is generated from vaping α-T-acetate that is highly toxic to epithelial cells, without lipid-loading of macrophages. Our long term goal is to identify mechanisms for effects of vaping α-T-acetate on lungs and fever in youth and adults with EVALI. As a step towards our long- term goal, our central HYPOTHESIS is that vaping α-T-acetate generates a novel high molecular weight toxic compound that induces lung inflammation, lung damage and fever in youth and adults, without lipid-loading lung macrophages. We will test this with the following aims: Aim 1. Test the hypothesis that a novel high molecular weight compound is generated from vaping α-T-acetate as assessed by mass spectrometry (MS), chemical structure modeling and NMR. Aim 2. Test the hypothesis that a novel compound, generated by vaping α-T- acetate, induces fever, lung damage, lung inflammation and reduces lung function, without lipid-loading of lung macrophages. We will also assess regulation of these manifestations by the early recruitment of lung eosinophils. Completion of these studies 1) will have a significant impact on our understanding of mechanisms of vaped α-T- acetate-induced lung damage and inflammation and 2) may lead to design of future human studies for interventions that significantly impact risk for EVALI and death from vaping in youths and adults.
