TY - JOUR
T1 - Cigarette smoke and nicotine-containing electronic-cigarette vapor downregulate lung WWOX expression, which is associated with increased severity of murine acute respiratory distress syndrome
AU - Zeng, Zhenguo
AU - Chen, Weiguo
AU - Moshensky, Alexander
AU - Shakir, Zaid
AU - Khan, Raheel
AU - Crotty Alexander, Laura E.
AU - Ware, Lorraine B.
AU - Aldaz, C. M.
AU - Jacobson, Jeffrey R.
AU - Dudek, Steven M.
AU - Natarajan, Viswanathan
AU - Machado, Roberto F.
AU - Singla, Sunit
N1 - Funding Information:
Supported by the services of the Cardiovascular Research Core at the University of Illinois in Chicago. Funding sources include the Natural National Science Foundation of China (81760351 and 81870011) (Z.Z) and the U.S. National Institutes of Health (HL126176 and HL103836) (L.B.W.); R01-HL-127342, R01-HL-133951, and 2R01 HL111656-06 (R.F.M.); and 1K08 HL140222-01A1 (S.S.).
Publisher Copyright:
Copyright © 2021 by the American Thoracic Society
PY - 2021/1
Y1 - 2021/1
N2 - 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 CD311 CD452cells. 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.
AB - 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 CD311 CD452cells. 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.
KW - ARDS
KW - Cigarette smoke
KW - E-cigarettes
KW - Endothelium
KW - WWOX
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U2 - 10.1165/rcmb.2020-0145OC
DO - 10.1165/rcmb.2020-0145OC
M3 - Article
C2 - 33058734
AN - SCOPUS:85098663155
SN - 1044-1549
VL - 64
SP - 89
EP - 99
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 1
ER -