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Aop: 280

AOP Title

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α-diketone-induced bronchiolitis obliterans

Short name:

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α-diketone-induced bronchiolitis obliterans

Graphical Representation

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Click to download graphical representation template

Authors

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Jan Boeij, Harry Vrielingh, Pieter Hiemstra, Inga Tluczkiewicz

Point of Contact

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Marvin Martens   (email point of contact)

Contributors

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  • Marvin Martens

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on January 30, 2019 10:00

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Revision dates for related pages

Page Revision Date/Time
Interaction of α-diketones with arginine residues January 30, 2019 10:23
Proteasomal dysfunction January 30, 2019 10:24
Airway epithelial injury January 30, 2019 10:25
Increase, Inflammation January 30, 2019 10:26
Induction, Epithelial Mesenchymal Transition January 30, 2019 10:27
Fibroproliferative airway lesions January 30, 2019 10:28
Bronchiolitis obliterans January 30, 2019 10:28
Interaction of α-diketones with arginine residues leads to Proteasomal dysfunction January 30, 2019 10:41
Proteasomal dysfunction leads to Airway epithelial injury January 30, 2019 10:42
Airway epithelial injury leads to Increase, Inflammation January 30, 2019 10:43
Increase, Inflammation leads to EMT January 30, 2019 10:58
Increase, Inflammation leads to Fibroproliferative airway lesions January 30, 2019 10:57
EMT leads to Fibroproliferative airway lesions January 30, 2019 10:59
Fibroproliferative airway lesions leads to Bronchiolitis obliterans January 30, 2019 11:01

Abstract

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Bronchiolitis obliterans (BO) is a severe respiratory illness due to the obstruction of the smallest airways of the lungs, the bronchioles. Inhalation of the -diketone diacetyl has been associated with the development of this disease in employees of the microwave popcorn production industry. Exposure of laboratory animals to diacetyl as well as other α-diketones results in airway epithelial injury, ultimately resulting in BO-like lesions. The electrophilic α-diketones interact with arginine residues causing altered structure and functioning of proteins. However, the critical proteins causing the observed toxicity have not yet been identified. Upon severe or repeated exposure to α-diketones the epithelium of the airways becomes severely damaged or the airways become completely denuded. In these injured regions of the airways the intrinsic regenerative capacity of the epithelium, via proliferation of basal cells and subsequent differentiation, is lost. This leads to compensatory proliferation in the adjacent mesenchyme in which fibroblast to myofibroblast transition may take place under the influence of inflammatory signals. Another possible cause of fibrogenesis is through the occurrence of epithelial-mesenchymal transition (EMT) within the injured airway epithelium. Excessive proliferation of fibrotic cells leads to the occlusion of the bronchioles resulting in dry cough, wheezing, shortness of breath and a strongly reduced lung function, the symptoms of BO.

This AOP is linked to EU-ToxRisk case study “ RDT: Popcorn Lung – read-across on diketones” in which the effects of α-diketone exposures are investigated using ex-vivo human precision cut lung slices and primary human bronchial epithelial cells cultured at the air-liquid interface.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1584 Interaction of α-diketones with arginine residues Interaction of α-diketones with arginine residues
2 KE 1585 Proteasomal dysfunction Proteasomal dysfunction
3 KE 1586 Airway epithelial injury Airway epithelial injury
4 KE 149 Increase, Inflammation Increase, Inflammation
5 KE 1457 Induction, Epithelial Mesenchymal Transition EMT
6 KE 1587 Fibroproliferative airway lesions Fibroproliferative airway lesions
7 AO 1588 Bronchiolitis obliterans Bronchiolitis obliterans

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Interaction of α-diketones with arginine residues leads to Proteasomal dysfunction adjacent Not Specified Not Specified
Proteasomal dysfunction leads to Airway epithelial injury adjacent Not Specified Not Specified
Airway epithelial injury leads to Increase, Inflammation adjacent Not Specified Not Specified
Increase, Inflammation leads to EMT adjacent Not Specified Not Specified
Increase, Inflammation leads to Fibroproliferative airway lesions adjacent Not Specified Not Specified
EMT leads to Fibroproliferative airway lesions adjacent Not Specified Not Specified
Fibroproliferative airway lesions leads to Bronchiolitis obliterans adjacent Not Specified Not Specified

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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