Abstract
BackgroundThe Wnt pathway mediates differentiation of epithelial tissues; depending on the tissue types, Wnt can either drive or inhibit the differentiation process. We hypothesized that key genes in the Wnt pathway are suppressed in the human airway epithelium under the stress of cigarette smoking, a stress associated with dysregulation of the epithelial differentiated state.Methodology/Principal FindingsMicroarrays were used to assess the expression of Wnt-related genes in the small airway epithelium (SAE) obtained via bronchoscopy and brushing of healthy nonsmokers, healthy smokers, and smokers with COPD. Thirty-three of 56 known Wnt-related genes were expressed in the SAE. Wnt pathway downstream mediators β-catenin and the transcription factor 7-like 1 were down-regulated in healthy smokers and smokers with COPD, as were many Wnt target genes. Among the extracellular regulators that suppress the Wnt pathway, secreted frizzled-related protein 2 (SFRP2), was up-regulated 4.3-fold in healthy smokers and 4.9-fold in COPD smokers, an observation confirmed by TaqMan Real-time PCR, Western analysis and immunohistochemistry. Finally, cigarette smoke extract mediated up-regulation of SFRP2 and down-regulation of Wnt target genes in airway epithelial cells in vitro.Conclusions/SignificanceSmoking down-regulates the Wnt pathway in the human airway epithelium. In the context that Wnt pathway plays an important role in differentiation of epithelial tissues, the down-regulation of Wnt pathway may contribute to the dysregulation of airway epithelium differentiation observed in smoking-related airway disorders.
Highlights
The human airway epithelium, a pseudostratified layer of cells derived from the endoderm, serves as a physical barrier against inhaled pathogens, xenobiotics, and other noxious substances in the environment [1,2]
There were no differences with respect to gender among the groups (p.0.3), but the COPD smokers were older than the other groups (p,0.05)
The data demonstrate that the majority of genes involved in the Wnt signaling pathway, representing all functional categories in the pathway, are expressed in the normal adult human small airway epithelium of healthy nonsmokers, consistent with studies showing the Wnt pathway can regulate human lung morphogenesis [11,24,25]
Summary
The human airway epithelium, a pseudostratified layer of cells derived from the endoderm, serves as a physical barrier against inhaled pathogens, xenobiotics, and other noxious substances in the environment [1,2]. Components of the canonical Wnt signaling pathway are expressed in embryonic and adult lung cell lines, as well as in the developing lung in a specific, spatio-temporal pattern [11,15,16,17]. When the canonical Wnt pathway is suppressed, undifferentiated progenitor cells are allowed to proceed toward differentiation [18,19,20,21,22,23]. When the SFRPs and/or DKKs are up-regulated, the Wnt pathway is suppressed, allowing differentiation to proceed [28,29]. We hypothesized that key genes in the Wnt pathway are suppressed in the human airway epithelium under the stress of cigarette smoking, a stress associated with dysregulation of the epithelial differentiated state
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