API

Relationship: 1839

Title

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Increase, Inflammation leads to Fibroproliferative airway lesions

Upstream event

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Increase, Inflammation

Downstream event

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Fibroproliferative airway lesions

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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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 Supporting this KER

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Biological Plausibility

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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.

Empirical Evidence

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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

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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.

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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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