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The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures and thus an interesting candidate gene for the study of exposure-related lung disease. Lungs harvested from current versus former\/never-smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle-treated controls. In separate studies, endothelial (EC)-specific WWOX knockout (KO) versus WWOX flox control mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31+ CD45\u2212cells. These were grown in culture, confirmed to be WWOX deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing as well as an FITC dextran transwell assay for their barrier properties during methicillin-resistant Staphylococcus aureus or LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to cells from WWOX flox controls during either methicillin-resistant S. aureus or LPS treatment as measured by both electric cell impedance sensing and the transwell assay. The increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.<\/jats:p>","DOI":"10.1165\/rcmb.2020-0145oc","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T19:35:57Z","timestamp":1602790557000},"page":"89-99","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":20,"title":["Cigarette Smoke and Nicotine-Containing Electronic-Cigarette Vapor Downregulate Lung WWOX Expression, Which is Associated with Increased Severity of Murine Acute Respiratory Distress Syndrome"],"prefix":"10.1093","volume":"64","author":[{"given":"Zhenguo","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Moshensky","sequence":"additional","affiliation":[{"name":"University of California, San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaid","family":"Shakir","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raheel","family":"Khan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Crotty Alexander","sequence":"additional","affiliation":[{"name":"University of California, San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine B.","family":"Ware","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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