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A7112 - ATP Binding Cassette (ABC) Transporter Expression in Human Airway Epithelial Cells: A Meta-Analysis of Gene Expression from Bronchial Brushings
Author Block: J. A. Hirota1, A. Tamminga1, J. A. Aguiar2, B. Lobb2, A. Dvorkin-Gheva3, A. C. Doxey2; 1Medicine, McMaster University, Hamilton, ON, Canada, 2Biology, Waterloo University, Waterloo, ON, Canada, 3Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
Rationale: A relative paucity of literature has explored the gene expression and function on ATP Binding Cassette (ABC) transporters in human airway epithelial cells. We have recently identified the expression and characterized the function of ABCC4 in human airway epithelial cells as a uric acid and cyclic AMP (cAMP) transporter (Gold-2016-Mucosal Immunology, Huff-2017-JACI, Ahmadi-2017-Genomic Medicine) with important consequences on respiratory mucosal immunology. The expression and function of many of the 48 ABC transporters remain completely unexplored in human airway epithelial cells.
Methods: To begin our discovery work, we searched PubMed and Gene Expression Omnibus for gene expression datasets generated from fresh bronchial brushings collected from healthy subjects and those with COPD (GSE11906, 11784, 4498, 37147, 994) or asthma (GSE67142, 4302, 63142, 76227). For a perspective of expression throughout the human body, relative gene expression of the 48 known human ABC transporters was compared between 27 human tissues. A Wilcoxon-signed rank test was performed to analyze differential gene expression between datasets with a Benjamini-Hochberg adjustment for multiple comparisons. In vitro experiments with the Calu-3 human airway epithelial cell line were performed to validate select findings.
Results: Our analysis revealed detectable gene expression levels of all 48 known human ABC transporters in human airway epithelial cells, varying along the airway tree. In response to cigarette smoke exposure, ABCC1, ABCC3, and ABCB6 were increased and ABCA13 decreased in three independent cohorts. ABCC1 expression was further increased in smokers with COPD. Smoking cessation reduced ABCC1, ABCB6, and ABCC3 expression. In asthmatics, ABCC1 and ABCC2 were increased and ABCA13 decreased in two independent cohorts. ABCA13 expression levels were negatively correlated with asthma severity.
Conclusions: We have recently demonstrated the ability of ABCC4 to transport uric acid and cAMP in human airway epithelial cells with implications in respiratory mucosal immunity. In our discovery meta-analysis using bronchial brushings from well-phenotyped healthy controls, smokers, individuals with COPD, and asthmatics, we reveal expression patterns of select ABC transporters that vary in response to cigarette smoking, disease status, and disease severity. The expression of ABCC1 correlated with smoking and COPD status, while ABCA13 expression was correlated with an inflammatory lung phenotype.