4.6 Article

Cigarette Smoke and Nicotine-Containing Electronic-Cigarette Vapor Downregulate Lung WWOX Expression, Which Is Associated with Increased Severity of Murine Acute Respiratory Distress Syndrome

Journal

Publisher

AMER THORACIC SOC
DOI: 10.1165/rcmb.2020-0145OC

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Funding

  1. Cardiovascular Research Core at the University of Illinois in Chicago
  2. Natural National Science Foundation of China [81760351, 81870011]
  3. U.S. National Institutes of Health [HL126176, HL103836, R01-HL-127342, R01-HL-133951, 2R01 HL111656-06, 1K08 HL140222-01A1]

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Chronic cigarette smoking is known to increase risk for ARDS, but the risks associated with chronic e-cigarette use are largely unknown. The WWOX gene is highly susceptible to genotoxic stress from environmental exposures and exposure to nicotine-containing e-cigarette vapor resulted in a decrease in WWOX mRNA levels. The downregulation of WWOX may play a role in the increased risk for ARDS in chronic smokers and potentially in chronic e-cigarette users in the future.
A history of chronic cigarette smoking is known to increase risk for acute respiratory distress syndrome (ARDS), but the corresponding risks associated with chronic e-cigarette use are largely unknown. 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(-) cells. 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.

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