API

Relationship: 1837

Title

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Proteasomal dysfunction leads to Airway epithelial injury

Upstream event

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Proteasomal dysfunction

Downstream event

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Airway epithelial injury

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
α-diketone-induced bronchiolitis obliterans adjacent Not Specified Not Specified

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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The covalent binding of α-diketones with arginine residues can alter the functioning of proteins. When this interaction affects critical proteins, cellular functioning becomes compromised and might eventually lead to cell death.

Evidence Supporting this KER

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Biological Plausibility

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When critical proteins are affected by the binding of α-diketones the functioning of cells in the airway epithelium becomes compromised and these cells cannot perform their specific task or might eventually die. The damaged epithelium might become devoid of the most sensitive cell-types, might lose its barrier function or the airways might even become locally denuded from an epithelial layer.

Empirical Evidence

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Inhalation of α-diketones by laboratory animals result in severe damage of the airway epithelium (Hubbs et al. 2012, Morgan et al. 2012, 2016). Also exposure of in vitro models of airway epithelium to α-diketones leads to a complete destruction of the epithelial layer (Zaccone et al. 2015, Foster et al. 2017).

Uncertainties and Inconsistencies

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At present the sensitivity of the individual cell types of the airway epithelium upon exposure to α-diketones is largely unknown.

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Hubbs, A. F., Cumpston, A. M., Goldsmith, W. T., Battelli, L. A., Kashon, M.

L., Jackson, M. C., Frazer, D. G., Fedan, J. S., Goravanahally, M. P., Castranova, V., Kreiss, K., Willard, P. A., Friend, S., Schwegler-Berry, D., Fluharty, K. L., and Sriram, K. (2012). Respiratory and olfactory cytotoxicity of inhaled 2,3-pentanedione in Sprague-Dawley rats. Am J Pathol 181, 829–44.

Foster, M. W., Gwinn, W. M., Kelly, F. L., Brass, D. M., Valente, A. M., Moseley, M. A., … Palmer, S. M. (2017). Proteomic Analysis of Primary Human Airway Epithelial Cells Exposed to the Respiratory Toxicant Diacetyl. Journal of Proteome Research, 16(2), 538–549. https://doi.org/10.1021/acs.jproteome.6b00672

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

Morgan, D. L., Jokinen, M. P., Johnson, C. L., Gwinn, W. M., Price, H. C., and

Flake, G. P. (2012). Bronchial fibrosis in rats exposed to 2,3-butanedione

and 2,3-pentanedione vapors. Toxicologist 126, 200.

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

Zaccone, E. J., Goldsmith, W. T., Shimko, M. J., Wells, J. R., Schwegler-Berry, D., Willard, P. A., … Fedan, J. S. (2015). Diacetyl and 2,3-pentanedione exposure of human cultured airway epithelial cells: Ion transport effects and metabolism of butter flavoring agents. Toxicology and Applied Pharmacology, 289, 542–549. https://doi.org/10.1016/j.taap.2015.10.004