Abstract
The apical junctional complex (AJC), composed of tight and adherens junctions, maintains epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating airway epithelial AJC integrity. Transcriptome analysis revealed global down-regulation of physiological AJC gene expression in the airway epithelium of healthy smokers (n = 59) compared to nonsmokers (n = 53) in association with changes in canonical epithelial differentiation pathways such as PTEN signaling accompanied by induction of cancer-related AJC components. The overall expression of AJC-related genes was further decreased in COPD smokers (n = 23). Exposure of airway epithelial cells to cigarette smoke extract in vitro resulted in down-regulation of several AJC genes paralleled by decreased transepithelial resistance. Thus, cigarette smoking induces transcriptional reprogramming of airway epithelial AJC architecture from its physiological pattern necessary for barrier function toward a disease-associated molecular phenotype.
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Abbreviations
- AJC:
-
Apical junctional complex
- AJ:
-
Adherens junctions
- CDH:
-
Cadherin
- CGN:
-
Cingulin
- CLDN:
-
Claudin
- COPD:
-
Chronic obstructive pulmonary disease
- CSE:
-
Cigarette smoke extract
- GO:
-
Gene ontology
- IAJC :
-
Small airway epithelium apical junctional complex gene expression index
- PCA:
-
Principal component analysis
- PTEN:
-
Phosphatase and tensin homolog
- SAE:
-
Small airway epithelium
- TJ:
-
Tight junctions
- TJP:
-
Tight junction protein
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Acknowledgments
We thank R.J. Kaner, A.E. Tilley, M.W. Butler, M. O’Mahony, B. Witover and B. Ferris for help with this study, and N. Mohamed for help in preparing the manuscript. These studies were supported, in part, by NIH R01 HL074326; P50 HL084936 and UL1-RR024996.
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Shaykhiev, R., Otaki, F., Bonsu, P. et al. Cigarette smoking reprograms apical junctional complex molecular architecture in the human airway epithelium in vivo. Cell. Mol. Life Sci. 68, 877–892 (2011). https://doi.org/10.1007/s00018-010-0500-x
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DOI: https://doi.org/10.1007/s00018-010-0500-x