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

Xu, Honghao; Ferro, Thomas J.; Chu, Shijian

doi:10.1183/09031936.00014107

Cited by 16 publications

(14 citation statements)

References 34 publications

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“…In the current study, two cell lines were included to permit assessing effects at various transformational stages and to meet the need to examine results in more than one cell line. The CSC dose range used, although difficult to compare with that in human airways in smokers, is similar to those previously reported in other in vitro studies (0 – 125 μg/ml) [23-26]. Additionally, the average yield of CSC was 26.1 mg/cigarette.…”

Section: Resultssupporting

confidence: 70%

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Effect of cigarette smoke condensate on gene promoter methylation in human lung cells

Lyn‐Cook¹,

Word²,

George³

et al. 2014

Tobacco Induced Diseases

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BackgroundIn lung cancer, an association between tobacco smoking and promoter DNA hypermethylation has been demonstrated for several genes. However, underlying mechanisms for promoter hypermethylation in tobacco-induced cancer are yet to be fully established.MethodsPromoter methylation was evaluated in control and cigarette smoke condensate (CSC) exposed human lung cells using the Methyl-Profiler DNA Methylation PCR System. PSAE cells were exposed to 0.3 or 1.0 μg/ml CSC for 72 hours and longer term for 14 and 30 days. NL-20 cells were exposed for 30 days to 10 or 100 μg/ml CSC.ResultsPromoters of several genes, including hsa-let-7a-3, CHD1, CXCL12, PAX5, RASSF2, and TCF21, were highly methylated (>90%); hsa-let-7a-3 was affected in both cell lines and under all exposure conditions. Level of methylation tended to increase with CSC concentration and exposure duration (statistical differences were not determined). Percentage methylation of TCF21, which was >98% at exposures of 10 or 100 μg/ml CSC, was found to be reduced to 28% and 42%, respectively, in the presence of the dietary agent genistein.ConclusionsUsing array techniques, several tumor suppressor genes in human lung cells were identified that undergo promoter hypermethylation, providing further evidence of their potential involvement in tobacco smoke-induced lung carcinogenesis and their use as potential biomarkers of harm in tobacco smoke exposure. Results from the study also demonstrated the potential of a dietary agent to exert chemopreventive activity in human tissue against tobacco smoke related diseases through modulation of DNA methylation. Additional studies are needed to confirm these findings.

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Section: Resultssupporting

confidence: 70%

“…CSC is widely used in model systems to study in vitro effects of tobacco smoke [23-26]. A disadvantage is that cell culture models often do not exhibit all the differentiated and functional characteristics of the corresponding native epithelium or the entire organ.…”

Section: Resultsmentioning

confidence: 99%

Effect of cigarette smoke condensate on gene promoter methylation in human lung cells

Lyn‐Cook¹,

Word²,

George³

et al. 2014

Tobacco Induced Diseases

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“…By using both H441 and Calu-3 cells, we show that this inhibition is present in more than one cell line with well-preserved lung epithelial characteristics. H 2 O 2 -induced changes in ␣-subunit variants were not detected in HAE cells (32), suggesting that the response to H 2 O 2 could be cell line-dependent. The finding that H 2 O 2 inhibits ␣-subunit expression in H441 and Calu-3 cells will help us in the evaluation of cell physiology data derived from H441 and Calu-3 monolayers under oxidative stress.…”

Section: Discussionmentioning

confidence: 95%

ENaC α-subunit variants are expressed in lung epithelial cells and are suppressed by oxidative stress

Xu¹,

Chu²

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Amiloride-sensitive epithelial sodium channel (ENaC) is a major sodium channel in the lung facilitating fluid absorption. ENaC is composed of alpha-, beta-, and gamma-subunits, and the alpha-subunit is indispensable for ENaC function in the lung. In human lungs, the alpha-subunit is expressed as various splice variants. Among them, alpha(1)- and alpha(2)-subunits are two major variants with different upstream regulatory sequences that possess similar channel characteristics when tested in Xenopus oocytes. Despite the importance of alpha-ENaC, little was known about the relative abundance of its variants in lung epithelial cells. Furthermore, lung infection and inflammation are often accompanied by reduced alpha-ENaC expression, oxidative stress, and pulmonary edema. However, it was not clear how oxidative stress affects expression of alpha-ENaC variants. In this study, we examined relative expression levels of alpha-subunit variants in four human lung epithelial cell lines. We also tested the hypothesis that oxidative stress inhibits alpha-ENaC expression. Our results show that both alpha(1)- and alpha(2)-ENaC variants are expressed in the cells we tested, but relative abundance varies. In the two monolayer-forming cell lines, H441 and Calu-3, alpha(2)-ENaC is the predominant variant. We also show that H(2)O(2) specifically suppresses alpha(1)- and alpha(2)-ENaC variant expression in H441 and Calu-3 cells in a dose-dependent fashion. This suppression is achieved by inhibition of their promoters and is attenuated by dexamethasone. These data demonstrate the importance of the alpha(2)-subunit variant and suggest that glucocorticoids and antioxidants may be useful in correcting infection/inflammation-induced lung fluid imbalance.

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“…Studies in human subjects and animal models have demonstrated that asymptomatic smokers have significantly greater lung epithelial permeability, a pathophysiological hallmark of ALI, as compared with nonsmokers (7-10). Active smoking also decreases expression of the primary ion channels responsible for resolving alveolar edema, which could impair alveolar fluid clearance and thus increase formation of lung edema (38,39). Likewise, both endothelial injury and disordered platelet function are thought to be critical to the pathogenesis of ALI (40,41), and the cardiovascular literature has demonstrated the potent effects of both active and secondhand smoke on both of these processes (16).…”

Section: Discussionmentioning

confidence: 99%

Active and Passive Cigarette Smoking and Acute Lung Injury after Severe Blunt Trauma

Calfee¹,

Matthay²,

Eisner³

et al. 2011

Am J Respir Crit Care Med

137

120

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Rationale: Cigarette smoking has been demonstrated in laboratory studies to have effects on lung epithelial and endothelial function similar to those observed in acute lung injury (ALI). However, the association between active and passive cigarette smoke exposure and susceptibility to ALI has not been prospectively studied. Objectives: We hypothesized that both active and passive cigarette smoke exposure would be associated with increased susceptibility to ALI after severe blunt trauma. Methods: We measured levels of cotinine, a metabolite of nicotine and validated biomarker of tobacco use, in plasma samples obtained immediately on arrival at the emergency department from 144 adult subjects after severe blunt trauma. Patients were then followed for the development of ALI. Measurements and Main Results: Increasing quartiles of plasma cotinine were associated with the development of ALI (odds ratio [OR] for developing ALI in highest cotinine quartile, 3.25; 95% confidence interval [CI], 1.22-8.68; P 5 0.017 for trend across quartiles). Moderate to heavy passive smoke exposure was associated with nearly the same odds of developing ALI as active smoking (OR for moderate to heavy passive smoking compared with no exposure or low level exposure, 3.03; 95% CI, 1.15-8.04; OR for active smoking, 2.77; 95% CI, 1. 28-5.99). This association persisted after adjusting for other predictors of ALI, including Injury Severity Score and alcohol abuse. Conclusions: Both moderate to heavy passive smoking and active smoking are independently associated with the development of ALI after severe blunt trauma. This finding has important implications both for public health and for understanding the pathogenesis of ALI.

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

Cited by 16 publications

References 34 publications

Effect of cigarette smoke condensate on gene promoter methylation in human lung cells

Effect of cigarette smoke condensate on gene promoter methylation in human lung cells

ENaC α-subunit variants are expressed in lung epithelial cells and are suppressed by oxidative stress

Active and Passive Cigarette Smoking and Acute Lung Injury after Severe Blunt Trauma

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