Airway basal cell injury after acute diacetyl (2, 3-butanedione) vapor exposure. (1st June 2020)

• Record Type: Journal Article
• Authors: McGraw, Matthew D.; Kim, So-Young; Reed, Christina; Hernady, Eric; Rahman, Irfan; Mariani, Thomas J.; Finkelstein, Jacob N.
• Is Part Of: Toxicology letters. Volume 325(2020)
• Page Start: 25
• Page End: 33
• Publication Date: 2020-06-01
• Subjects: Diacetyl -- Airway epithelium -- Keratin 5 -- Ubiquitin proteasome -- Epithelial repair -- Flavoring-Induced lung disease; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2020.02.012
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: Diacetyl vapor exposure causes airway basal cell injury with keratin 5 ubiquitination and decreased ΔNp63 expression. Airway epithelial repair after diacetyl vapor exposure occurs through ubiquitination and subsequent proteasome degradation of keratin 5 protein damage. Inhibition of the ubiquitin-proteasome pathway after diacetyl vapor exposure results in impaired clearance of keratin 5 ubiquitinated proteins. Abstract: Rationale: Diacetyl (DA; 2, 3-butanedione) is a chemical found commonly in foods and e-cigarettes. When inhaled, DA causes epithelial injury, though the mechanism of repair remain poorly understood. The objective of this study was to evaluate airway basal cell repair after DA vapor exposure. Methods: Primary human bronchial epithelial cells were exposed to DA or PBS for 1 h. Lactate dehydrogenase, cleaved caspase 3/7 and trans-epithelial electrical resistance were measured prior to and following exposure. Exposed cultures were analyzed for the airway basal cell markers keratin 5 and p63 as well as ubiquitin and proteasome activity. Cultures were also treated with a proteasome inhibitor (MG132). Results: DA vapor exposure caused a transient decrease in trans-epithelial electrical resistance in all DA-exposed cultures. Supernatant lactate dehydrogenase and cleaved caspase 3/7 increased significantly at the highest DA concentration but not at lower DA concentrations. Increased keratin 5 ubiquitination occurred after DA exposure but resolved by day 3. Damage to airway basal cells persisted at day 3 in the presence of MG132. Conclusions: Diacetyl exposure results in airway basal cell injury with keratin 5 ubiquitination and decreased p63 expression. The ubiquitin-proteasome-pathway partially mediates airway basal cell repair after acute DA exposure.