Reversible and permanent effects of tobacco smoke exposure on airway epithelial gene expression

Bioinformatics Program, Boston University, Cummington Street, Boston, MA 02215, USA.
Genome biology (Impact Factor: 10.81). 02/2007; 8(9):R201. DOI: 10.1186/gb-2007-8-9-r201
Source: PubMed


Tobacco use remains the leading preventable cause of death in the US. The risk of dying from smoking-related diseases remains elevated for former smokers years after quitting. The identification of irreversible effects of tobacco smoke on airway gene expression may provide insights into the causes of this elevated risk.
Using oligonucleotide microarrays, we measured gene expression in large airway epithelial cells obtained via bronchoscopy from never, current, and former smokers (n = 104). Linear models identified 175 genes differentially expressed between current and never smokers, and classified these as irreversible (n = 28), slowly reversible (n = 6), or rapidly reversible (n = 139) based on their expression in former smokers. A greater percentage of irreversible and slowly reversible genes were down-regulated by smoking, suggesting possible mechanisms for persistent changes, such as allelic loss at 16q13. Similarities with airway epithelium gene expression changes caused by other environmental exposures suggest that common mechanisms are involved in the response to tobacco smoke. Finally, using irreversible genes, we built a biomarker of ever exposure to tobacco smoke capable of classifying an independent set of former and current smokers with 81% and 100% accuracy, respectively.
We have categorized smoking-related changes in airway gene expression by their degree of reversibility upon smoking cessation. Our findings provide insights into the mechanisms leading to reversible and persistent effects of tobacco smoke that may explain former smokers increased risk for developing tobacco-induced lung disease and provide novel targets for chemoprophylaxis. Airway gene expression may also serve as a sensitive biomarker to identify individuals with past exposure to tobacco smoke.

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    • "Comparability of in vivo/in vitro responses to CS exposure. To determine correlations between the effects of CS exposure in vitro and the effects of smoking in vivo, the network perturbation scores of the Xenobiotic Metabolism Response network (Iskandar et al., 2013) generated from the in vitro datasets (CSexposed vs air-exposed organotypic tissues) were compared with those generated from publicly available in vivo datasets (smokers vs nonsmokers in large airway brushing samples): GGSE7895 (Beane et al., 2007); GSE160058 (Zhang et al., 2010); and GSE14633 (Schembri et al., 2009). "
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    ABSTRACT: Organotypic three dimensional cultures of epithelial cells are grown at the air-liquid interface (ALI) and resemble the in vivo counterparts. Although the complexity of in vivo cellular responses could be better manifested in co-culture models in which additional cell-types such as fibroblasts were incorporated, the presence of another cell-type could mask the response of the other. This study reports the impact of whole cigarette smoke (CS) exposure on organotypic mono- and co-culture models to evaluate the relevancy of organotypic models for toxicological assessment of aerosols. Two organotypic bronchial models were directly exposed to low and high concentrations of CS of the reference research cigarette 3R4F: mono-culture of bronchial epithelial cells without fibroblasts (BR) and co-culture with fibroblasts (BRF) models. Adenylate kinase-based cytotoxicity, cytochrome P450 (CYP) 1A1/1B1 activity, tissue histology, and concentrations of secreted mediators into the basolateral media, as well as transcriptomes were evaluated following the CS exposure. The results demonstrated similar impact of CS on the AK-based cytotoxicity, CYP1A1/1B1 activity, and tissue histology in both models. However, a greater number of secreted mediators was identified in the basolateral media of the mono-culture than in the co-culture models. Furthermore, annotation analysis and network-based systems biology analysis of the transcriptomic profiles indicated a more prominent cellular stress and tissue damage following CS in the mono-culture epithelium model without fibroblasts. Finally, our results indicated that an in vivo smoking-induced xenobiotic metabolism response of bronchial epithelial cells was better reflected from the in vitro CS-exposed co-culture model. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email:
    Toxicological Sciences 06/2015; 147(1). DOI:10.1093/toxsci/kfv122 · 3.85 Impact Factor
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    • "and Butcher, 2002; Keith and Miller, 2013; Schembri et al., 2009; Boyle et al., 2010; Beane et al., 2007; Zhang et al., 2010; Harvey et al., 2007 "
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    ABSTRACT: High-throughput sequencing of RNA (RNA-Seq) was developed primarily to analyze global gene expression in different tissues. It is also an efficient way to discover coding SNPs and when multiple individuals with different genetic backgrounds were used, RNA-Seq is very effective for the identification of SNPs. The objective of this study was to perform SNP and INDEL discoveries in human airway transcriptome of healthy never smokers, healthy current smokers, smokers without lung cancer and smokers with lung cancer. By preliminary comparative analysis of these four data sets, it is expected to get SNP and INDEL patterns responsible for lung cancer. A total of 85,028 SNPs and 5738 INDELs in healthy never smokers, 32,671 SNPs and 1561 INDELs in healthy current smokers, 50,205 SNPs and 3008 INDELs in smokers without lung cancer and 51,299 SNPs and 3138 INDELs in smokers with lung cancer were identified. The analysis of the SNPs and INDELs in genes that were reported earlier as differentially expressed was also performed. It has been found that a smoking person has SNPs at position 62,186,542 and 62,190,293 in SCGB1A1 gene and 180,017,251, 180,017,252, and 180,017,597 in SCGB3A1 gene and INDELs at position 35,871,168 in NFKBIA gene and 180,017,797 in SCGB3A1 gene. The SNPs identified in this study provides a resource for genetic studies in smokers and shall contribute to the development of a per-sonalized medicine. This study is only a preliminary kind and more vigorous data analysis and wet lab validation are required.
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    • "In a number of gene expression trials, microscopically normal bronchial epithelium from patients harboring lung cancer has been shown to possess altered transcriptome (27). Importantly, while some of these changes are reversible others are permanent, consonant with the long-term risk of lung cancer even after smoking cessation (28). From a diagnostic point of view, the study of Spira and colleagues was pivotal for having identified 80 gene biomarkers from the microscopically normal right mainstem bronchus that could discriminate between smokers with and without lung cancer with 80% sensitivity and 84% specificity (29). "
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    ABSTRACT: MicroRNAs (miRNAs) have been shown to be reliable early biomarkers in a variety of cancers including that of lung. We ascertained whether the biomarker potential of miRNAs could be validated in microscopically normal and easily accessible buccal epithelial brushings from cigarette smokers as a consequence of lung cancer linked 'field carcinogenesis'. We found that compared to neoplasia-free subjects, a panel of 68 miRNAs were upregulated and 3 downregulated in the normal appearing buccal mucosal cells collected from patients harboring lung cancer (n=76). The performance characteristics of selected miRNAs (with ≥1-fold change) were excellent with an average under the receiver operator characteristic curve (AUROC) of >0.80. Several miRNAs also displayed gender specificity between the groups. These results provide the first proof-of-concept scenario in which minimally intrusive cheek brushings could provide an initial screening tool in a large at-risk population.
    International Journal of Oncology 06/2014; DOI:10.3892/ijo.2014.2495 · 3.03 Impact Factor
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