Upstream eventFibroproliferative airway lesions
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|α-diketone-induced bronchiolitis obliterans||adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
Excessive proliferation of fibrotic cells and the deposition of extracellular matrix leads to the occlusion of the lumen of the smaller airways.
The occlusion of the lumen of the smaller airways (the bronchioles) results in dry cough, wheezing, shortness of breath and a strongly reduced lung function, the symptoms of bronchiolitis obliterans.
Evidence Supporting this KER
Uncontrolled proliferation of myofibroblast in the airway regions suffering from damaged epithelium and the deposition of extracellular matrix leads to narrowing of the airway lumen or even the complete occlusion of the bronchioles.
Occlusion of the smaller airways blocks the flow of air into and out of the lungs. This leads to a reduced gas exchange and a compromised lung function.
In patients suffering from bronchiolitis obliterans and in animal models to study this disease, occlusion of the smaller airways is observed (Morgan et al. 2016, Rose, 2017). Actually, this occlusion is a hallmark of the disease. In the regions of obstruction, fibrotic tissue with excessive deposition of extracellular matrix is typically observed.
Concentric narrowing of the lumen of the bronchioles by the inflammatory fibrosis is the hallmark of bronchiolitis obliterans. In some regions there may even be complete occlusion of the lumen. Also in laboratory animals (rats) exposed to a-diketones, fibrotic occlusion of the airways is observed.
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Morgan, D. L., Jokinen, M. P., Johnson, C. L., Price, H. C., Gwinn, W. M., Bousquet, R. W., & Flake, G. P. (2016). Chemical Reactivity and Respiratory Toxicity of the alpha-Diketone Flavoring Agents: 2,3-Butanedione, 2,3-Pentanedione, and 2,3-Hexanedione. Toxicologic Pathology, 44(5), 763–783. https://doi.org/10.1177/0192623316638962
Rose, C. S. (2017). Early detection, clinical diagnosis, and management of lung disease from exposure to diacetyl. Toxicology, 388, 9–14. https://doi.org/10.1016/j.tox.2017.03.019