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Epidemiological and clinical evidence suggests a role of vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized VEA causes lung injury in mice and directly injures human alveolar epithelial cells, we exposed adult mice and primary human alveolar epithelial type II (AT II) cells to an aerosol of VEA generated by a device designed for vaping oils. Outcome measures in mice included lung edema, BAL analysis, histology, and inflammatory cytokines; in vitro outcomes included cell death, cytokine release, cellular uptake of VEA, and gene-expression analysis. Comparison exposures in both models included the popular nicotine-containing JUUL aerosol. We discovered that VEA caused dose-dependent increases in lung water and BAL protein compared with control and JUUL-exposed mice in association with increased BAL neutrophils, oil-laden macrophages, multinucleated giant cells, and inflammatory cytokines. VEA aerosol was also toxic to AT II cells, causing increased cell death and the release of monocyte and neutrophil chemokines. VEA was directly absorbed by AT II cells, resulting in the differential gene expression of several inflammatory biological pathways. Given the epidemiological and clinical characteristics of the EVALI outbreak, these results suggest that VEA plays an important causal role.<\/jats:p>","DOI":"10.1165\/rcmb.2020-0209oc","type":"journal-article","created":{"date-parts":[[2020,8,21]],"date-time":"2020-08-21T13:51:16Z","timestamp":1598017876000},"page":"748-757","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":62,"title":["Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate"],"prefix":"10.1093","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4995-8442","authenticated-orcid":false,"given":"Shotaro","family":"Matsumoto","sequence":"first","affiliation":[{"name":"Department of Medicine and"},{"name":"Department of Anesthesia, Cardiovascular Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"Department of Anesthesia, Cardiovascular Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maret G.","family":"Traber","sequence":"additional","affiliation":[{"name":"Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk D.","family":"Jones","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Langelier","sequence":"additional","affiliation":[{"name":"Linus Pauling Institute, College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon; and"},{"name":"Chan Zuckerberg Biohub, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Hayakawa Serpa","sequence":"additional","affiliation":[{"name":"Linus Pauling Institute, College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn S.","family":"Calfee","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"Department of Anesthesia, Cardiovascular Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Matthay","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"Department of Anesthesia, Cardiovascular Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey E.","family":"Gotts","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"Department of Anesthesia, Cardiovascular Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"key":"2026021100445590600_bib1","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1056\/NEJMoa1911614","article-title":"Pulmonary illness related to E-cigarette use in Illinois and Wisconsin - final report","volume":"382","author":"Layden","year":"2020","journal-title":"N Engl J Med"},{"key":"2026021100445590600_bib2","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1056\/NEJMc1913069","article-title":"Pathology of vaping-associated lung injury","volume":"381","author":"Butt","year":"2019","journal-title":"N Engl J Med"},{"key":"2026021100445590600_bib3","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1056\/NEJMc1912038","article-title":"Pulmonary lipid-laden macrophages and vaping","volume":"381","author":"Maddock","year":"2019","journal-title":"N Engl J Med"},{"key":"2026021100445590600_bib4","article-title":"NIH workshop report. 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