ArticleThe American journal of pathology2016
Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity.
Article in The American journal of pathology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 33 citations in OpenAlex.
- Targeting integrin beta 4 in diacetyl-induced anoikis of the airway epithelium.Cell death discovery · 2026Article
- Discovery of a Human Metabolite That Mimics the Bacterial Quorum-Sensing Autoinducer AI-2.Journal of the American Chemical Society · 2026Article
- Diacetyl-induced bronchiolitis obliterans involves ubiquitin C upregulation and fibrosis-related gene activation in rats.Frontiers in pharmacology · 2025Article
- Molecular Mechanisms Underlying Neuroinflammation Elicited by Occupational Injuries and Toxicants.International journal of molecular sciences · 2023Review
- Diacetyl inhalation impairs airway epithelial repair in mice infected with influenza A virus.American journal of physiology. Lung cellular and molecular physiology · 2022Article
- Xenobiotics Delivered by Electronic Nicotine Delivery Systems: Potential Cellular and Molecular Mechanisms on the Pathogenesis of Chronic Kidney Disease.International journal of molecular sciences · 2022Review
- Dicarbonyl/L-xylulose reductase (DCXR) producing xylitol regulates egg retention through osmolality control inAnimal cells and systems · 2022Article
- Diacetyl Vapor Inhalation Induces Mixed, Granulocytic Lung Inflammation with Increased CD4Toxics · 2021Article
- Repetitive diacetyl vapor exposure promotes ubiquitin proteasome stress and precedes bronchiolitis obliterans pathology.Archives of toxicology · 2021Article
- Formation of Diacetyl and Other α-Dicarbonyl Compounds during the Generation of E-Vapor Product Aerosols.ACS omega · 2020Article
- Airway basal cell injury after acute diacetyl (2,3-butanedione) vapor exposure.Toxicology letters · 2020Article
- Pulmonary Impairment and Risk Assessment in a Diacetyl-Exposed Population: Microwave Popcorn Workers.Journal of occupational and environmental medicine · 2018Article
- Models of toxicity of diacetyl and alternative diones.Toxicology · 2017Review
- Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells.Chemical research in toxicology · 2017Article
- The Diacetyl-Exposed Human Airway Epithelial Secretome: New Insights into Flavoring-Induced Airways Disease.American journal of respiratory cell and molecular biology · 2017Article
- Proteomic Analysis of Primary Human Airway Epithelial Cells Exposed to the Respiratory Toxicant Diacetyl.Journal of proteome research · 2017Article
- Diacetyl exposure disrupts iron homeostasis in animals and cells.Inhalation toxicologyArticle
Corrections and comments
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Authors and funding
27 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inhaled diacetyl vapors are associated with flavorings-related lung disease, a potentially fatal airway disease. The reactive α-dicarbonyl group in diacetyl causes protein damage in vitro. Dicarbonyl/l-xylulose reductase (DCXR) metabolizes diacetyl into acetoin, which lacks this α-dicarbonyl group. To investigate the hypothesis that flavorings-related lung disease is caused by in vivo protein damage, we correlated diacetyl-induced airway damage in mice with immunofluorescence for markers of protein turnover and autophagy. Western immunoblots identified shifts in ubiquitin pools. Diacetyl inhalation caused dose-dependent increases in bronchial epithelial cells with puncta of both total ubiquitin and K63-ubiquitin, central mediators of protein turnover. This response was greater in Dcxr-knockout mice than in wild-type controls inhaling 200 ppm diacetyl, further implicating the α-dicarbonyl group in protein damage. Western immunoblots demonstrated decreased free ubiquitin in airway-enriched fractions. Transmission electron microscopy and colocalization of ubiquitin-positive puncta with lysosomal-associated membrane proteins 1 and 2 and with the multifunctional scaffolding protein sequestosome-1 (SQSTM1/p62) confirmed autophagy. Surprisingly, immunoreactive SQSTM1 also accumulated in the olfactory bulb of the brain. Olfactory bulb SQSTM1 often congregated in activated microglial cells that also contained olfactory marker protein, indicating neuronophagia within the olfactory bulb. This suggests the possibility that SQSTM1 or damaged proteins may be transported from the nose to the brain. Together, these findings strongly implicate widespread protein damage in the etiology of flavorings-related lung disease.
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