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EMT leads to Fibroproliferative airway lesions
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|α-diketone-induced bronchiolitis obliterans||adjacent||Not Specified||Not Specified||Marvin Martens (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
In the absence of normal regeneration of damaged airway epithelium, dysregulated repair by epithelial cells that underwent epithelial-mesenchymal transition or by differentiated mesenchymal fibroblasts takes place. Excessive proliferation of the fibrotic cells and the deposition of extracellular matrix results in fibroproliferative lesions seen the smaller airways of patients suffering from bronchiolitis obliterans.
Evidence Collection Strategy
Evidence Supporting this KER
Damage to the airway epithelium is usually efficiently repaired by proliferation and subsequent differentiation of specific airway progenitor cells. However, upon severe or repeated damage induction these progenitor cells become locally depleted. Under these conditions, adjacent mesenchymal proliferation is observed as an alternative way to repair the local injury. This dysregulated repair is characterized by excessive proliferation causing fibroproliferative airway lesions.
In damaged airways of a-diketone exposed laboratory animals excessive proliferation of myofibroblasts is observed together with substantial deposition of extracellular matrix (Morgan et al 2016, Flake et al. 2017). Also in rats exposed to sulfur mustard, other agents damaging the epithelial layer of the airways (and causing bronchiolitis obliterans), persistent altered epithelial morphology was observed with sub-epithelial proliferation and significant collagen deposition (McGraw et al. 2017).
Uncertainties and Inconsistencies
Important insight in the development of bronchiolitis obliterans after a-diketone exposure is obtained using rats. Typically biopsies of the lungs are analysed for the presence of structural alterations in the respiratory tract. These biopsies are snapshots taken during the development of OB-like lesions. It is difficult to extract insight in the factors crucial during the gradual development of the observed fibroproliferative lesions.
Known modulating factors
Quantitative Understanding of the Linkage
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
Flake, G. P., & Morgan, D. L. (2017). Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. Toxicology, 388, 40–47. https://doi.org/10.1016/j.tox.2016.10.013
McGraw, M. D., Rioux, J. S., Garlick, R. B., Rancourt, R. C., White, C. W., & Veress, L. A. (2017). Impaired proliferation and differentiation of the conducting airway epithelium associated with bronchiolitis obliterans after sulfur mustard inhalation injury in rats. Toxicological Sciences, 157(2), 399–409. https://doi.org/10.1093/toxsci/kfx057