Cigarette smoke condensate inhibits ENaC α-subunit expression in lung epithelial cells

Cigarette smoke has been associated with lung fluid accumulation and increased risk of acute respiratory distress syndrome. It was postulated that ENaC a-subunit, which plays a critical role in lung fluid absorption, is affected by cigarette smoke. Cigarette smoke condensate (CSC) was used to treat a human lung epithelial cell line. ENaC a-subunit expression was measured using immunoblotting, quantitative PCR and promoterreporter assays. The current authors found that CSC, without affecting cell survival, suppressed a-subunit expression at the transcriptional level in a dose- and time-dependent fashion. This suppression is neither related to nicotine nor due to an increase of hydrogen peroxide levels in CSC-treated cells. CSC also suppressed a-subunit core promoter activity. Dexamethasone, which activates the core promoter, was able to attenuate the inhibitory effect of CSC. However, in the presence of CSC, dexamethasone was unable to elicit a full-scale activation of a-subunit expression. This inhibition of dexamethasone was partially reversed by withdrawal of CSC. The present results demonstrate that cigarette smoke condensate inhibits ENaC a-subunit expression at the transcriptional level through its promoter. This inhibition could be reversed by dexamethasone. The results also suggest that higher doses of dexamethasone may be needed to activate a-subunit expression in smokers' lungs compared with nonsmokers' lungs, and that quitting smoking might improve the effectiveness of dexamethasone.