Interaction of α-diketones with arginine residues

600-14-6

TZMFJUDUGYTVRY-UHFFFAOYSA-N

2,3-Pentanedione

ACETYL PROPIONYL Acetylpropionyl NSC 7613 Pentan-2,3-dion Pentane-2,3-dione pentano-2,3-diona

DTXSID6051435

431-03-8

QSJXEFYPDANLFS-UHFFFAOYSA-N

2,3-Butanedione

Dimethyl glyoxal Diacetyl 2,3-Butadione 2,3-Diketobutane 2,3-Dioxobutane Biacetyl BUTA-2,3-DIONE Butandion Butanedione butanodiona Dimethyl diketone Dimethylglyoxal NSC 8750 UN 2346

DTXSID6021583

GO:0006954

GO inflammatory response

WIKI increased

2,3-Pentanedione

2019-01-30T10:14:06

2,3-Butanedione

2019-01-30T10:22:48

9606

NCBI Homo sapiens

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

Interaction of α-diketones with arginine residues

Molecular

The electrophilic α-diketones interact with proteins via direct covalent binding to cellular nucleophiles. The interaction occurs predominantly with the arginine residues of proteins.

The binding of α-diketones with proteins can be measured by LC-MS and 1H- and 13C NMR analysis (Anders 2017, Mathews et al. 2010, Saraiva et al. 2016)

Anders, M. W. (2017). Diacetyl and related flavorant α-Diketones: Biotransformation, cellular interactions, and respiratory-tract toxicity. Toxicology, 388, 21–29. <a href="https://doi.org/10.1016/j.tox.2017.02.002">https://doi.org/10.1016/j.tox.2017.02.002</a> Mathews, J. M., Watson, S. L., Snyder, R. W., Burgess, J. P., & Morgan, D. L. (2010). Reaction of the butter flavorant diacetyl (2,3-Butanedione) with N-??-acetylarginine: A model for epitope formation with pulmonary proteins in the etiology of obliterative bronchiolitis. Journal of Agricultural and Food Chemistry, 58(24), 12761–12768. <a href="https://doi.org/10.1021/jf103251w">https://doi.org/10.1021/jf103251w</a> More, S. S., Raza, A., & Vince, R. (2012). The butter flavorant, diacetyl, forms a covalent adduct with 2-deoxyguanosine, uncoils DNA, and leads to cell death. Journal of Agricultural and Food Chemistry, 60(12), 3311–3317. <a href="https://doi.org/10.1021/jf300180e">https://doi.org/10.1021/jf300180e</a> Saraiva, M. A., Borges, C. M., & Helena Flor??ncio, M. (2016). Mass spectrometric studies of the reaction of a blocked arginine with diketonic ??-dicarbonyls. Amino Acids, 48(3), 873–885. <a href="https://doi.org/10.1007/s00726-015-2135-6">https://doi.org/10.1007/s00726-015-2135-6</a> AOPWiki 2019-01-30T09:31:49

2019-01-30T10:23:47

Proteasomal dysfunction

Molecular

The covalent interaction of α-diketones with arginines leads to altered structure and functioning of proteins. Indication of widespread protein damage was observed in DA exposed mice (Hubbs et al. 2016)

The inactivation of enzymes due to the interaction of α-diketones with arginine residues at their active sites has been demonstrated (Chen and Chen 2003). Protein damage has been measured by accumulation of ubiquitin and sequestosome-1 in the lungs of exposed mice (Hubbs et al. 2016)

Chen, G., Chen, X., 2003. Arginine residues in the active site of human phenol sulfotransferase (SULT1A1). J. Biol. Chem. 278, 36358–36364. Hubbs, A. F., Fluharty, K. L., Edwards, R. J., Barnabei, J. L., Grantham, J. T., Palmer, S. M., … Sriram, K. (2016). Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity. In American Journal of Pathology (Vol. 186, pp. 2887–2908). <a href="https://doi.org/10.1016/j.ajpath.2016.07.018">https://doi.org/10.1016/j.ajpath.2016.07.018</a> More, S.S., et al., 2012a. The butter flavorant, diacetyl, forms a covalent adduct with 2-deoxyguanosine, uncoils DNA, and leads to cell death. J. Agric. Food Chem. 60, 3311–3317. AOPWiki 2019-01-30T09:32:24

2019-01-30T10:24:24

Airway epithelial injury

Cellular

Inhalation of to low concentrations of α-diketones generally does not result in airway injury. However, above a certain threshold the airway epithelium becomes persistently damaged.

Histopathological abnormalities in exposed rats, airway epithelial necrosis, flattening of the airway epithelial cells, loss of cilia (Foster et al. 2017), gaps in the epithelial layer (Hubbs et al. 2002, 2008). Also a reduced expression of club cell secretory protein in airway epithelium has been observed after a-diketone exposure (Palmer et al. 2011). Within in vitro models of airway epithelium, the loss of epithelial barrier function following exposure can be measured as a reduction in transepithelial electrical resistance (TEER, Fedan et al. 2006, Zaccone et al 2015)

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. <a href="https://doi.org/10.1021/acs.jproteome.6b00672">https://doi.org/10.1021/acs.jproteome.6b00672</a> Hubbs, A. F., Goldsmith, W. T., Kashon, M. L., Frazer, D., Mercer, R. R., Battelli, L. A., … Castranova, V. (2008). Respiratory Toxicologic Pathology of Inhaled Diacetyl in Sprague-Dawley Rats. Toxicologic Pathology, 36(2), 330–344. https://doi.org/10.1177/0192623307312694 Palmer, S. M., Flake, G. P., Kelly, F. L., Zhang, H. L., Nugent, J. L., Kirby, P. J., … Morgan, D. L. (2011). Severe airway epithelial injury, aberrant repair and Bronchiolitis obliterans develops after diacetyl instillation in rats. PLoS ONE, 6(3). https://doi.org/10.1371/journal.pone.0017644 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 AOPWiki 2019-01-30T09:32:52

2019-01-30T10:25:29

Increase, Inflammation

Cellular

Inflammation is complex to define.  Villeneuve et al. (2018) analyzed the varied biological responses, provided guidance to simplify the  process representing inflammation in adverse outcome pathways, and recommended 3 key steps: 1. Tissue resident cell activation 2. Increased Pro-inflammatory mediators 3. Leukocyte recruitment/activation.  Tissue resident cell activation generally occurs when healthy tissue is exposed to a stressor, or when damage occurs, initiating a signal response of pro-inflammatory mediators (ex. cytokines).  Pro-inflammatory mediators result in the production of lipids and proteins, signaling, and initiate leukocyte recruitment/activation.  Leukocyte recruitment/activation initiate inflammation and other morphological changes.  Some empirical research studies that illustrate inflammation pathways: <ul> <li>A review of inflammation caused by microplastics in mammals (Wright and Kelly, 2017).  Inflammation and immune responses are caused by irritation via microplastics inhalation.</li> <li>Increased inflammatory interleukin gene expression in lab mice brains with damaged hypoglossal nerves (Gamo et al., 2008).  Inflammatory genes interleukin-1beta and interleukin-6, and tumor necrosis factor-alpha levels were increased after physical injury.</li> <li>Increased inflammation in the freshwater fish Danio rerio exposed to polystyrene microplastics (Lu et al., 2016).  Oxidative stress indicator enzymes superoxide dismutase and catalase were increased in livers, along with histopathological changes in inflammation and necrosis, in response to accumulation of microplastics.</li> <li>Inhibited inflammatory interleukin gene expression in guts and increased mucus production in guts in the freshwater fish Danio rerio exposed to polystyrene microplastics (Jin et al., 2018).  Gene expression of tumor necrosis factor-alpha, interleukin-1alpha, interleukin-1beta, interferon, interleukin-6, interleukin-8, interleukin-10 were changed, with most genes showing statistically significant increases and a dose-response relationship, due to exposure to polystyrene microplastics.  In additional, gut microbiota was altered.</li> <li>Significant intestinal damage including intestinal fold disruption, enterocyte damage, broken tissue, and inflammation in the freshwater fish Danio rerio exposed to microplastics (Lei et al., 2018).  Growth and reproductive effects were seen in addition to the histology observations, and associated with accumulation of microplastics.</li> </ul> In cancer, inflammation is a cascade of events created by the host in response to the spread of the cancer (Coussens and Werb, 2002). In response to an injury or the presence of cancer, the host heals itself through inflammation. Indeed, the activation and the migration of  leukocytes (neutrophils, monocytes and eosinophils) to the wound induces the healing process. These inflammatory cells provide an extracellular matrix that forms upon which fibroblast and endothelial cells proliferate and migrate in order to recreate a normal environment. Damage to the epithelial layer initiate inflammatory reactions (Palmer et al. 2011).  In cancer, this inflammatory state induces cell proliferation, increases the production of reactive oxygen species leading to oxidative DNA damage, and reduces DNA repair (Coussens and Werb, 2002).

Inflammation is generally detected in histopathological examination of organs (ex. liver, intestines) or in changes in gene expression (ex. interleukins).  Activation of the innate immune response and the release of various inflammatory cytokines can also be assessed (Flake and Morgan, 2017).

Taxonomic: appears to be present broadly, with representative studies focused on mammals (humans, lab mice, lab rats).

CL:0000255

CL eukaryotic cell

High Unspecific

High

All life stages

High High High

Flake, G.P., and Morgan, D.L. 2017. Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. Toxicology, 388, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013">https://doi.org/10.1016/j.tox.2016.10.013</a> Palmer, S.M., Flake, G.P., Kelly, F.L., Zhang, H.L., Nugent, J.L., Kirby, P.J., Zhang, H.L., Nugent, J.L., Kirby, P.J., Foley, J.F., Gwinn, W.M., and Morgan, D.L. 2011. Severe airway epithelial injury, aberrant repair and Bronchiolitis obliterans develops after diacetyl instillation in rats. PLoS ONE, 6(3). <a href="https://doi.org/10.1371/journal.pone.0017644">https://doi.org/10.1371/journal.pone.0017644</a> Coussens L.M. and Werb Z. Inflammation and cancer. Nature. 2002 Dec 19-26;420(6917):860-7. doi: 10.1038/nature01322. PMID: 12490959; PMCID: PMC2803035. Gamo, K., Kiryu-Seo, S., Konishi, H., Aoki, S., Matushima, K., Wada, K., and Kiyama, H.  2008.  G-protein-coupled receptor screen reveals a role for chemokine recepteor CCR5 in suppressing microglial neurotoxicity.  Journal of Neuroscience 28: 11980-11988. Jin, Y., Xia, J., Pan, Z., Yang, J., Wang, W., and Fu, Z.  2018.  Polystyrene microplastics induce microbiota dysbiosis and inflammation in the gut of adult zebrafish.  Environmental Pollution 235: 322-329. Lei, L., Wu, S., Lu, S., Liu, M., Song, Y., Fu, Z., Shi, H., Raley-Susman, K.M., and He, D.  2018.  Microplastic particles cause intestinal damage and other adverse effects in zebrafish Danio rerio and nematode Caenorhabditis elegans.  Science of the Total Environment 619-620: 1-8. AOPWiki 2016-11-29T18:41:23

2023-08-10T14:43:51

Induction, Epithelial Mesenchymal Transition

EMT

Cellular

Inflammatory reactions result in the release of various cytokines which in turn can stimulate the transition of epithelial cells to a mesenchymal phenotype acquiring function characteristics of fibroblasts and myofibroblasts.

Loss of <a href="https://en.wikipedia.org/wiki/E-cadherin">E-cadherin</a> and cell polarity is considered to be a fundamental event in epithelial-mesenchymal transition. The simultaneous expression of epithelial (e.g. E-cadherin) and mesenchymal markers (e.g. N-cadherin and vimentin) within the airway epithelium are indicative for ongoing transition (Borthwick et al. 2009, 2010).

Borthwick, L. A., Parker, S. M., Brougham, K. A., Johnson, G. E., Gorowiec, M. R., Ward, C., … Fisher, A. J. (2009). Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation. Thorax, 64(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133">https://doi.org/10.1136/thx.2008.104133</a> Borthwick, L. A., McIlroy, E. I., Gorowiec, M. R., Brodlie, M., Johnson, G. E., Ward, C., … Fisher, A. J. (2010). Inflammation and epithelial to mesenchymal transition in lung transplant recipients: Role in dysregulated epithelial wound repair. American Journal of Transplantation, 10(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x">https://doi.org/10.1111/j.1600-6143.2009.02953.x</a> AOPWiki 2017-07-26T19:11:33

2019-01-30T10:27:22

Fibroproliferative airway lesions

Tissue

Repeated exposure to α-diketones might result in the loss of the regenerative capacity of the airway epithelium, e.g. due to insufficient residual stem cells. Sustained loss of the epithelial cells might lead to damage to the underlying basement membrane and exposure of the lamina propria. Fibroblast in the lamina propria are activated and start to proliferate and elaborate collagen matrix. Cytokines and growth factors released by epithelial cells and infiltrated neutrophils may promote the migration and proliferation of fibroblasts into the airway lumen. The initially fibromyxoid tissue is gradually replaced by mature connective tissue that is rich in collagen (rats, Flake & Morgan 2017).

Fibroproliferative airway lesions can be observed in biopsies of α-diketone exposed laboratory animals in a dose dependent manner using various tissue stainings of histological specimen. (rats, Morgan et al. 2016, Flake & Morgan 2017)

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. <a href="https://doi.org/10.1016/j.tox.2016.10.013">https://doi.org/10.1016/j.tox.2016.10.013</a> 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 AOPWiki 2019-01-30T09:44:24

2019-01-30T10:28:20

Bronchiolitis obliterans

Individual

Bronchiolitis obliterans is a lung disease characterized by obstruction of the smallest airways of the lungs. The cumulative exposure to DA correlated with the degree of airway obstruction and the incidence of BO (Kreiss et al. 2002).

Forced expiratory volume in 1 second (FEV1) CT scan Thoracoscopic lung biopsy showing histological and morphological changes (human, King et al. 2011) Other typical symptoms include: dry cough, shortness of breath and wheezing.

Kreiss et al. 2002 (first report of DA induced BO) Kreiss 2014 (changes in the human lung after DA exposure) AOPWiki 2019-01-30T09:45:13

2019-01-30T10:28:55

<upstream-id>d3710cb6-bb14-408b-8a82-bf77f0fe2273</upstream-id> <downstream-id>7e2ffc53-4a0b-4c47-9c02-86f8c8db04ab</downstream-id> α-diketones are able to react with proteins, predominantly by covalent binding with arginine residues. This interaction with proteins can affect their structure and compromise their function. Arginine-rich proteins or enzymes with arginine residues at active sites are likely the critical molecular targets.

The toxic effects of the electrophilic α-diketones are likely associated with their direct covalent interactions with cellular nucleophiles. In this way, α-diketones react with proteins, displaying a great affinity for arginine residues. Since arginine residues are often located at the active sites of enzymes the interaction with α-diketones can cause loss of enzyme activity. Also the interaction with other proteins can result in altered structure and function.

The reaction of α-diketones with proteins has been known for decades (Harden en Norris, 1911). Also the selective interaction with arginine residues is well established (Mathews et al. 2010). Actually, the α-diketone diacetyl is used to identify functional arginine residues in enzymes (Chen and Chen, 2003). Besides the loss of enzyme activity the interaction with other proteins can also result in modification of protein structure and function (Ahmed and Thomalley, 2003). Furthermore, protein damage is implicated in the cytotoxicity observed after exposure to α-diketones (Hubbs et al. 2016). The reactivity of α-diketones depends on the carbon chain length. In general, the shorter the chain the higher the reactivity (Morgan et al. 2016, Xia et al. 1993).

The target proteins are likely arginine-rich proteins or enzymes containing arginine residues at their active sites. However, at present it is unclear which proteins are the critical targets for the observed toxicity after the inhalation of α-diketones.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ebbbc138> AOPWiki 2019-01-30T09:45:34

2019-01-30T10:41:36

<upstream-id>7e2ffc53-4a0b-4c47-9c02-86f8c8db04ab</upstream-id> <downstream-id>a2a14ce5-e2d4-4b35-a864-1d07852c48fc</downstream-id> 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.

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.

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).

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

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ebc3ae98> AOPWiki 2019-01-30T09:45:51

2019-01-30T10:42:53

<upstream-id>a2a14ce5-e2d4-4b35-a864-1d07852c48fc</upstream-id> <downstream-id>0d18ae97-585d-4214-a66b-710044686fb6</downstream-id> Damage of the airway epithelium leads to inflammatory reactions.

Inflammation is a biological response to harmful stimuli, including cell damage. Therefore, damage to airway epithelium will initiate inflammatory reactions.

Moderately damaged epithelium can regenerate itself after exposure cessation and the inflammatory reaction, initiated by the release of various inflammatory cytokines (Anderson et al. 2010), will be of limited duration. However, severely damaged epithelium is unable to recover, probably due to the depletion of progenitor cells required to regenerate the epithelium (McGraw et al. 2017). This leads to sustained inflammation. The inability of epithelium regeneration and the resulting chronic inflammation might explain the threshold for the manifestation of negative health effects typically observed after α-diketone inhalation.

It is clear that inflammatory reactions occur after exposure to α-diketones. The exact role of inflammation in the ultimate development of bronchiolitis obliterans remains unclear.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ebcdb528> AOPWiki 2019-01-30T09:46:10

2019-01-30T10:43:42

<upstream-id>0d18ae97-585d-4214-a66b-710044686fb6</upstream-id> <downstream-id>e55a557d-eb3d-44de-a3cc-e579de16eebc</downstream-id> The inflammatory reactions initiated by the damaged airway epithelium might stimulate the transition of fibroblasts present in the underlying mesenchymal tissue to myofibroblasts.

Fibroblast to myofibroblast transition might represent an alternative way, besides EMT, to close wounds in the epithelial layer. Under the influence of inflammatory signals, fibroblast present in the mesenchymal tissue beneath the damage epithelium might be stimulated to differentiate into myofibroblasts. Especially in regions of the airways that became completely denuded from an epithelial layer this might form an alternative for EMT to repair the wound in the epithelium.

Studying airway fibroblasts in vitro, myofibroblast transdifferentiation in response to TGF-beta1 signaling was observed, evidenced by increased alpha-smooth muscle actin mRNA and protein expression (Ramirez et al. 2006).

Both the transition of epithelial cells to mesenchymal cells as well as the transition of mesenchymal fibroblasts to myofibroblast are possible mechanisms leading to dysregulated repair of damage airway epithelium. At present it is unclear which transition is the most prominent.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ebeba6f0> AOPWiki 2018-03-18T09:50:09

2019-01-30T10:58:48

<upstream-id>0d18ae97-585d-4214-a66b-710044686fb6</upstream-id> <downstream-id>6ce11d87-1d7a-4299-a4f9-85ed742a5fc8</downstream-id> 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.

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).

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.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4311384490> AOPWiki 2019-01-30T09:46:43

2019-01-30T10:57:10

<upstream-id>e55a557d-eb3d-44de-a3cc-e579de16eebc</upstream-id> <downstream-id>6ce11d87-1d7a-4299-a4f9-85ed742a5fc8</downstream-id> 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.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43113a4420> AOPWiki 2019-01-30T09:57:47

2019-01-30T10:59:39

<upstream-id>6ce11d87-1d7a-4299-a4f9-85ed742a5fc8</upstream-id> <downstream-id>cd7dc35c-3575-4e6b-9e8f-a082e8efa6f8</downstream-id> 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.

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.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4311934020> AOPWiki 2019-01-30T10:00:08

2019-01-30T11:01:08

α-diketone-induced bronchiolitis obliterans

Agnes Aggy

Jan Boeij, Harry Vrielingh, Pieter Hiemstra, Inga Tluczkiewicz

BY-SA

2.0

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.

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AOPWiki 2019-01-30T09:26:02

2023-09-25T16:26:59