Abstract
BackgroundThe small airway epithelium (SAE), the cell population that covers the human airway surface from the 6th generation of airway branching to the alveoli, is the major site of lung disease caused by smoking. The focus of this study is to provide quantitative assessment of the SAE transcriptome in the resting state and in response to chronic cigarette smoking using massive parallel mRNA sequencing (RNA-Seq).ResultsThe data demonstrate that 48% of SAE expressed genes are ubiquitous, shared with many tissues, with 52% enriched in this cell population. The most highly expressed gene, SCGB1A1, is characteristic of Clara cells, the cell type unique to the human SAE. Among other genes expressed by the SAE are those related to Clara cell differentiation, secretory mucosal defense, and mucociliary differentiation. The high sensitivity of RNA-Seq permitted quantification of gene expression related to infrequent cell populations such as neuroendocrine cells and epithelial stem/progenitor cells. Quantification of the absolute smoking-induced changes in SAE gene expression revealed that, compared to ubiquitous genes, more SAE-enriched genes responded to smoking with up-regulation, and those with the highest basal expression levels showed most dramatic changes. Smoking had no effect on SAE gene splicing, but was associated with a shift in molecular pattern from Clara cell-associated towards the mucus-secreting cell differentiation pathway with multiple features of cancer-associated molecular phenotype.ConclusionsThese observations provide insights into the unique biology of human SAE by providing quantit-ative assessment of the global transcriptome under physiological conditions and in response to the stress of chronic cigarette smoking.
Highlights
The small airway epithelium (SAE), the cell population that covers the human airway surface from the 6th generation of airway branching to the alveoli, is the major site of lung disease caused by smoking
The tracheobronchial tree, a dichotomous branching structure that begins at the larynx and ends after 23 branches at the alveoli, is lined by an epithelium comprised of 4 major cell types, including ciliated, secretory, undifferentiated columnar and basal cells [1,2]
Our group [11,12,13] and others [14,15,16,17,18] have carried out several studies using gene expression microarrays to assess the transcriptome of the human airway epithelium, demonstrating that smoking modulates the expression of hundreds of genes
Summary
The small airway epithelium (SAE), the cell population that covers the human airway surface from the 6th generation of airway branching to the alveoli, is the major site of lung disease caused by smoking. The focus of this study is to provide quantitative assessment of the SAE transcriptome in the resting state and in response to chronic cigarette smoking using massive parallel mRNA sequencing (RNA-Seq). The advent of RNA-Seq technology, in which the entire polyadenylated transcriptome is sequenced [19,20,21,22,23,24], is capable of building on this microarray data to provide additional insights into the transcriptome of the airway epithelium and its response to cigarette smoke. In the context of this background, the focus of this study is to utilize massive parallel sequencing to quantify the complete transcriptome of the human SAE in healthy nonsmokers and healthy smokers
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