Regulation of xanthine dehydrogensase gene expression and uric acid production in human airway epithelial cells

• Published in: PloS one Vol. 12; no. 9; p. e0184260
• Main Authors: Huff, Ryan D, Hsu, Alan C-Y, Nichol, Kristy S, Jones, Bernadette, Knight, Darryl A, Wark, Peter A B, Hansbro, Philip M, Hirota, Jeremy A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-09-2017; Public Library of Science (PLoS)
• Subjects: Acid production; Acids; Adult; Aged; Allergens; Allopurinol; Animal models; Animals; Antioxidants; Asthma; Asthma - metabolism; Binding sites; Biology and Life Sciences; Bronchi - cytology; Bronchi - drug effects; Cell culture; Cells, Cultured; Chronic illnesses; Chronic obstructive pulmonary disease; Cigarette smoke; Cytokines; Damage patterns; Disease; Disease Models, Animal; Environmental effects; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelium; Exposure; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Genetic aspects; House dust; Humans; Immunology; In vitro methods and tests; Inflammation; Influenza; Inhibitors; Interferon-gamma - pharmacology; Lung diseases; Lungs; Male; Medical research; Medicine; Medicine and Health Sciences; Metabolism; Metabolites; Mice; Mice, Inbred BALB C; Middle Aged; Obstructive lung disease; Patients; Physical Sciences; Physiological aspects; Production methods; Proteins; Pulmonary Disease, Chronic Obstructive - metabolism; Pyroglyphidae; Research and Analysis Methods; Respiratory diseases; Respiratory tract; Smoke; Smoking; Tobacco Products; Tumor necrosis factor; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Uric acid; Uric Acid - metabolism; Xanthine; Xanthine dehydrogenase; Xanthine Dehydrogenase - metabolism; γ-Interferon; Australia; Canada; Vancouver British Columbia Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0184260

The airway epithelium is a physical and immunological barrier that protects the pulmonary system from inhaled environmental insults. Uric acid has been detected in the respiratory tract and can function as an antioxidant or damage associated molecular pattern. We have demonstrated that human airway epithelial cells are a source of uric acid. Our hypothesis is that uric acid production by airway epithelial cells is induced by environmental stimuli associated with chronic respiratory diseases. We therefore examined how airway epithelial cells regulate uric acid production.
Allergen and cigarette smoke mouse models were performed using house dust mite (HDM) and cigarette smoke exposure, respectively, with outcome measurements of lung uric acid levels. Primary human airway epithelial cells isolated from clinically diagnosed patients with asthma and chronic obstructive pulmonary disease (COPD) were grown in submerged cultures and compared to age-matched healthy controls for uric acid release. HBEC-6KT cells, a human airway epithelial cell line, were grown under submerged monolayer conditions for mechanistic and gene expression studies.
HDM, but not cigarette smoke exposure, stimulated uric acid production in vivo and in vitro. Primary human airway epithelial cells from asthma, but not COPD patients, displayed elevated levels of extracellular uric acid in culture. In HBEC-6KT, production of uric acid was sensitive to the xanthine dehydrogenase (XDH) inhibitor, allopurinol, and the ATP Binding Cassette C4 (ABCC4) inhibitor, MK-571. Lastly, the pro-inflammatory cytokine combination of TNF-α and IFN-γ elevated extracellular uric acid levels and XDH gene expression in HBEC-6KT cells.
Our results suggest that the active production of uric acid from human airway epithelial cells may be intrinsically altered in asthma and be further induced by pro-inflammatory cytokines.