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

Introduction:
This text reports on a study examining the impact of cigarette smoke and nicotine-containing electronic-cigarette vapor on lung WWOX expression and its association with the severity of acute respiratory distress syndrome (aRDS) in mice.

Key Points:

* Lungs from mice exposed to nicotine-containing e-cigarette vapor exhibited an average 57% decrease in WWOX expression compared with controls.
* EC WWOX KO mice treated with LPS or MRSa exhibited greater amounts of leukocyte numbers, protein concentration, and FITC-dextran flux from the vascular space compared with LPS- or MRSa-treated WWOX flox mice.
* WWOX-silenced hLMVECs treated with LPS resulted in larger decreases in TER compared with wild-type cells.
* WWOX-silenced hLMVECs pretreated with the JNK inhibitor SP600125 before LPS resulted in no significant rescue of barrier function toward that of wild-type cells.
* WWOX expression has been noted in inflammatory cell types in addition to the major cell types of the lung, reducing the possibility that an influx of WWOX-deficient cell types artificially resulted in decreased WWOX expression as measured by RT-PCR.
* In the current study, inhibition of JNK did not appear to affect barrier susceptibility during WWOX knockdown, suggesting that c-Jun–related pathways are not a significant component of the underlying mechanism.
* The cell supernatant levels of inflammatory cytokines were elevated in MRSa-stimulated WWOX-deficient ECs compared with WWOX flox, suggesting that some of these may contribute to enhanced EC barrier disruption seen in WWOX-deficient ECs via autocrine effects.

Main Message:
The study found that downregulation of lung WWOX expression in mice exposed to nicotine-containing e-cigarette vapor and in EC WWOX KO mice treated with LPS or MRSa resulted in increased vascular leak and severity of aRDS. The findings suggest that lung WWOX expression may play a protective role in aRDS and that chronic exposure to nicotine-containing e-cigarette vapor may increase the risk and severity of aRDS during lung infection. Further research is needed to confirm the association and to define the relative importance of WWOX downregulation versus other e-cigarette-induced gene expression changes in mediating these potential risks.

Zeng Z, Chen W, Moshensky a, et al. Cigarette Smoke and Nicotine-Containing Electronic-Cigarette Vapor Downregulate Lung WWOX Expression, Which Is associated with Increased Severity of Murine acute Respiratory Distress Syndrome. american journal of respiratory cell and molecular biology. 2021;64(1):89-99. doi:10.1165/rcmb.2020-0145OC