600-14-6TZMFJUDUGYTVRY-UHFFFAOYSA-NTZMFJUDUGYTVRY-UHFFFAOYSA-N
2,3-PentanedioneACETYL PROPIONYL
Acetylpropionyl
NSC 7613
Pentan-2,3-dion
Pentane-2,3-dione
pentano-2,3-diona
DTXSID6051435431-03-8QSJXEFYPDANLFS-UHFFFAOYSA-NQSJXEFYPDANLFS-UHFFFAOYSA-N
2,3-ButanedioneDimethyl 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
DTXSID6021583GO:0006954inflammatory response1increased2,3-Pentanedione2019-01-30T10:14:062019-01-30T10:14:062,3-Butanedione2019-01-30T10:22:482019-01-30T10:22:489606Homo sapiens10090Mus musculus10116Rattus norvegicusWCS_9606humansInteraction of α-diketones with arginine residuesInteraction of α-diketones with arginine residuesMolecular<p>The electrophilic α-diketones interact with proteins via direct covalent binding to cellular nucleophiles. The interaction occurs predominantly with the arginine residues of proteins.</p>
<p>The binding of α-diketones with proteins can be measured by LC-MS and <sup>1</sup>H- and <sup>13</sup>C NMR analysis (Anders 2017, Mathews et al. 2010, Saraiva et al. 2016)</p>
<p>Anders, M. W. (2017). Diacetyl and related flavorant α-Diketones: Biotransformation, cellular interactions, and respiratory-tract toxicity. <em>Toxicology</em>, <em>388</em>, 21–29. <a href="https://doi.org/10.1016/j.tox.2017.02.002"><u>https://doi.org/10.1016/j.tox.2017.02.002</u></a></p>
<p>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. <em>Journal of Agricultural and Food Chemistry</em>, <em>58</em>(24), 12761–12768. <a href="https://doi.org/10.1021/jf103251w"><u>https://doi.org/10.1021/jf103251w</u></a></p>
<p>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. <em>Journal of Agricultural and Food Chemistry</em>, <em>60</em>(12), 3311–3317. <a href="https://doi.org/10.1021/jf300180e"><u>https://doi.org/10.1021/jf300180e</u></a></p>
<p>Saraiva, M. A., Borges, C. M., & Helena Flor??ncio, M. (2016). Mass spectrometric studies of the reaction of a blocked arginine with diketonic ??-dicarbonyls. <em>Amino Acids</em>, <em>48</em>(3), 873–885. <a href="https://doi.org/10.1007/s00726-015-2135-6"><u>https://doi.org/10.1007/s00726-015-2135-6</u></a></p>
2019-01-30T09:31:492019-01-30T10:23:47Proteasomal dysfunctionProteasomal dysfunctionMolecular<p>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)</p>
<p>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)</p>
<p>Chen, G., Chen, X., 2003. Arginine residues in the active site of human phenol sulfotransferase (SULT1A1). J. Biol. Chem. 278, 36358–36364.</p>
<p>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 <em>American Journal of Pathology</em> (Vol. 186, pp. 2887–2908). <a href="https://doi.org/10.1016/j.ajpath.2016.07.018"><u>https://doi.org/10.1016/j.ajpath.2016.07.018</u></a></p>
<p>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.</p>
2019-01-30T09:32:242019-01-30T10:24:24Airway epithelial injuryAirway epithelial injuryCellular<p>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.</p>
<p>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 <em>in vitro</em> 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)</p>
<p>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. <em>Journal of Proteome Research</em>, <em>16</em>(2), 538–549. <a href="https://doi.org/10.1021/acs.jproteome.6b00672"><u>https://doi.org/10.1021/acs.jproteome.6b00672</u></a></p>
<p>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. <em>Toxicologic Pathology</em>, <em>36</em>(2), 330–344. https://doi.org/10.1177/0192623307312694</p>
<p>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. <em>PLoS ONE</em>, <em>6</em>(3). https://doi.org/10.1371/journal.pone.0017644</p>
<p>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. <em>Toxicology and Applied Pharmacology</em>, <em>289</em>, 542–549. https://doi.org/10.1016/j.taap.2015.10.004</p>
2019-01-30T09:32:522019-01-30T10:25:29Increase, InflammationIncrease, InflammationCellular<p><span style="font-size:16px"><span style="font-family:Calibri,sans-serif">Inflammation is complex to define. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Calibri,sans-serif">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. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Calibri,sans-serif">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). For review of inflammation caused by microplastics in mammals, see Wright and Kelly (2017).</span></span></p>
<p> </p>
<p> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Inflammation can be defined as the response of the organism to a tissue injury (Coussens). Indeed, in order to heal this injury, a multitude of chemical signals initiate and maintain a host response. Leukocytes </span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">(neutrophils, monocytes and eosinophils)</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> are recruited to the site of the damage through the attraction by chemokines (</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">TNF-α (tumour necrosis factor-α)</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">, interleukines…). A </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">provisional extracellular matrix (ECM)</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> is created, and f</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">ibroblast and endothelial cells proliferate and migrate</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> to it. Wound healing is an example of physiological inflammation and is self-limiting (Coussens). In case of a dysregulation, inflammation can lead to pathologies. </span></span></span></span></span><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Inflammation can be </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">caused by physical injury, ischemic injury, infection, exposure to toxins, or other types of trauma</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> (Singh).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Inflammation was described as one of the hallmarks of cancer by Hannahan et al. as a response to tumor invasion through mainly two mechanisms: promoting genetic instatbility and supply pro-tumorogenic factors.</span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">First, inflammation in cancer promotes genetic instability (</span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">Mantovani</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">, colotta). Macrophages, in contact with the inflammatory site can be responsible of a reactive stress oxygen reaction (ROS) (</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">Maeda</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">, Pollard, </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Grivennikov</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">). Indeed, they </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">generate high levels of reactive oxygen and nitrogen species </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">which </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">produce mutagenic agents</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> (</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">peroxynitrite</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">)</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">, which </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">in turn </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">cause</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">s</span></span></span> <span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">DNA </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">mutation</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">s.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Second, </span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">in inflammation, the tumor micro environment plays a critical role (Coussens). Indeed, in can supply </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#505050">growth factors, survival factors, proangiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis, and inductive signals that lead to activation of EMT and other hallmark-facilitating programs</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#505050"> (Hannahan). For example, </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">macrophages can become tumor associated macrophage which promote </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">cell proliferation, angiogenesis, and invasio</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">n (Singh, Lin, Qian)</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Moreover, chronic inflammation can also lead to tumorigenesis (Karin, </span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Singh</span></span></span><span style="font-family:"Times New Roman",serif">). Indeed, since 1863, Virchow has hypothesized that chronic inflammation causes cell proliferation (Balkwill). </span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">According to Aggarwall, s</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">everal pro-inflammatory </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">markers</span></span></span> <span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">such as </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">TNF and members of its superfamily, IL-1alpha, IL-1beta, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX</span></span></span><span style="font-family:"Times New Roman",serif"> <span style="background-color:white"><span style="color:#212121">mediate</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> (Aggarwal).</span></span></span></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Calibri,sans-serif">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). </span></span></p>
<p> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">Several assays can be used to measure inflammation: </span></span></span></span></span></p>
<ul>
<li style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Histopathology on samples. Several scoring tools exist (Goeboes)</span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Measuring chemokines in the blood (</span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">ELISA, multiplex bead assays</span></span></span> <span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">: </span></span></span><span style="font-family:"Times New Roman",serif">interleukines (IL1, IL6), TNF, interferon… ) (Brenner) and histopathology samples</span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Measuring </span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Prostaglandin</span></span></span> <span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">levels, </span></span></span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">COX-2</span></span></span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> (</span></span></span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">ELISA</span></span></span><br />
<span style="font-family:"Times New Roman",serif"><span style="color:#212121"><span style="background-color:#fffcf0">Liquid chromatography/tandem mass spectrometry</span></span></span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">, IHC)</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Transcription factors : </span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">STAT3 Activation</span></span></span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">, </span></span></span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">NF-κB Activation</span></span></span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121"> (</span></span></span><span style="background-color:#fffcf0"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">ELISA</span></span></span><br />
<span style="font-family:"Times New Roman",serif"><span style="color:#212121"><span style="background-color:#fffcf0">RtPCR to measure mRNA</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Biomarkers (white cell count, CRP) ratios, and predictive score using </span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Measuring ROS(</span><span style="background-color:#d3e3fd"><span style="font-family:"Times New Roman",serif"><span style="color:#040c28">DCFDA</span></span></span><span style="background-color:#d3e3fd"><span style="font-family:"Times New Roman",serif"><span style="color:#040c28">, </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#222222">horseradish peroxidase (HRP)-oxidizing substrates</span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#222222">, </span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#222222">SOD-inhibitable reduction of cytochrome c</span></span></span><span style="background-color:#d3e3fd"><span style="font-family:"Times New Roman",serif"><span style="color:#040c28">) (Murphy).</span></span></span></span></span></li>
</ul>
<p style="margin-left:48px; text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Methods are extensively reviewed in Marchand et al and Murphy et al.</span></span></span></p>
<p><span style="font-size:16px"><span style="font-family:"Calibri",sans-serif">Taxonomic: appears to be present broadly, with representative studies focused on mammals (humans, lab mice, lab rats).</span></span></p>
<p> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif">Extensive data exists on the presence of inflammation in human</span><span style="font-family:"Times New Roman",serif"> (Coussens, Aggarwal, Hannhan, Mantovani..) In human, many examples of chronic inflammation leading to cancer or cancer progression exist. For instance, Helicobacter pylori infection leads to gut cancer (Wang).</span></span></span></p>
<p> </p>
CL:0000255eukaryotic cellHighUnspecificHighAll life stagesHighHighHigh<p><span style="font-size:16px">Flake, G.P., and Morgan, D.L. 2017. Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. <em>Toxicology</em>, <em>388</em>, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013"><u>https://doi.org/10.1016/j.tox.2016.10.013</u></a></span></p>
<p><span style="font-size:16px">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. <em>PLoS ONE</em>, <em>6</em>(3). <a href="https://doi.org/10.1371/journal.pone.0017644"><u>https://doi.org/10.1371/journal.pone.0017644</u></a></span></p>
<p> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014 Apr 10;345(2):196-202. doi: 10.1016/j.canlet.2013.08.016. Epub 2013 Aug 24. PMID: 23981572.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:15.0pt"><span style="background-color:white"><span style="font-family:"Cambria",serif"><span style="color:#303030">Naylor MS, Stamp GW, Foulkes WD, Eccles D, Balkwill FR. Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression. </span></span></span></span><em>J Clin Invest. </em>1993;91:2194–206.</span></span></p>
<p><span style="font-size:16px">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.</span></p>
<p><span style="font-size:16px"><span style="font-family:Calibri,sans-serif">Wright, S.L. and Kelly, F.J. 2017. Plastic and human health: a micro issue? Enviromental Science and Technology 51: 6634-6647.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Calibri,sans-serif">Villeneuve, D.L., Landesmann, B., Allavena, P., Ashley, N., Bal-Price, A., Corsini, E., Halappanavar, S., Hussell, T., Laskin, D., Lawrence, T., Nikolic-Paterson, D., Pallary, M., Paini, A., Pietrs, R., Roth, R., and Tschudi-Monnet, F. 2018. Toxicological Sciences 163(2): 346-352.</span></span></p>
<p> </p>
<p> </p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. </span></span></span><em>Nature. </em>2008;454:436–44</span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010 Mar 19;140(6):883-99. doi: 10.1016/j.cell.2010.01.025. PMID: 20303878; PMCID: PMC2866629.</span></span></span></span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#222222">Murphy, M.P., Bayir, H., Belousov, V. </span></span></span><em>et al.</em> Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. <em>Nat Metab</em> <strong>4</strong>, 651–662 (2022). <a href="https://doi.org/10.1038/s42255-022-00591-z" style="color:#467886; text-decoration:underline">https://doi.org/10.1038/s42255-022-00591-z</a></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Geboes K, Riddell R, Öst A<em>, et al</em></span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">A reproducible grading scale for histological assessment of inflammation in ulcerative colitis</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:Aptos,sans-serif"><em><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Gut </span></span></em><span style="font-family:"Times New Roman",serif"><span style="color:#333333">2000;<strong>47:</strong>404-409.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="background-color:white"><span style="font-family:Aptos,sans-serif"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Brenner DR, Scherer D, Muir K, Schildkraut J, Boffetta P, Spitz MR, Le Marchand L, Chan AT, Goode EL, Ulrich CM, Hung RJ. A review of the application of inflammatory biomarkers in epidemiologic cancer research. Cancer Epidemiol Biomarkers Prev. 2014 Sep;23(9):1729-51. doi: 10.1158/1055-9965.EPI-14-0064. Epub 2014 Jun 24. PMID: 24962838; PMCID: PMC4155060.</span></span></span></span></span></span></p>
2016-11-29T18:41:232024-02-28T06:33:44Induction, Epithelial Mesenchymal TransitionEMTCellular<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Process:transition of epithelial cells to mesenchymal Object: epithelial cells </span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> Action:increased</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Process:transition of epithelial cells to mesenchymal Object: epithelial cells </span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> Action:increased</span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Biological state</span></strong></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">An epithelial-mesenchymal transition (EMT) is a biologic process in which epithelial cells are polarized, interact through their basal surface with basement membrane, and undergo biochemical changes to assume a mesenchymal cell phenotype. </span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">This phenotypic transformation has various characters such as enhanced migratory capacity, high invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components (Kalluri, R., and Neilson, E.G. 2003). The completion of an EMT is signalled by the degradation of the underlying basement membrane and the formation of a mesenchymal cell that can migrate away from the epithelial layer in which it originated.</span></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black"> EMT has a number of distinct molecular processes like activation of transcription factors, expression of specific cell surface proteins, reorganization and expression of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in the expression of specific microRNAs. These factors are used as biomarkers to demonstrate the passage of a cell through an EMT. </span></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Biological compartment </span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Cellular</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Role in General Biology:</span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Excessive proliferation of epithelial cells and angiogenesis mark the initiation and early growth of primary epithelial cancers. (Hanahan, D., and Weinberg, R.A. 2000). The subsequent acquisition of invasiveness, initially manifest by invasion through the basement membrane, is thought to herald the onset of the last stages of the multi-step process that leads eventually to metastatic dissemination, with life-threatening consequences. There has been an intense research going on in the genetic controls and biochemical mechanisms underlying the acquisition of the invasive phenotype and the subsequent systemic spread of the cancer cell. Activation of an EMT program has been proposed as the critical mechanism for the acquisition of malignant phenotypes by epithelial cancer cells (Thiery, J.P. 2002).</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black"> Pre-clinical experiments such as mice models and cell culture experiments has demonstrated that carcinoma cells can acquire a mesenchymal phenotype and express mesenchymal markers such as </span><span style="color:black">α</span><span style="color:black">-SMA, FSP1, vimentin, and desmin (Yang, J., and Weinberg, R.A. 2008). These cells are seen at the invasive front of primary tumors and are considered to be the cells that eventually enter into subsequent steps of the invasion-metastasis cascade, i.e., intravasation, transport through the circulation, extravasation, formation of micro metastases, and ultimately colonization (the growth of small colonies into macroscopic metastases) (Thiery, J.P. 2002, Fidler, I.J., and Poste, G. 2008, Brabletz, T., et al. 2001).</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">An apparent paradox comes from the observation that the EMT-derived migratory cancer cells typically establish secondary colonies at distant sites that resemble, at the histopathological level, the primary tumor from which they arose; accordingly, they no longer exhibit the mesenchymal phenotypes ascribed to metastasizing carcinoma cells. Reconciling this behaviour with the proposed role of EMT as a facilitator of metastatic dissemination requires the additional notion that metastasizing cancer cells must shed their mesenchymal phenotype via a MET during the course of secondary tumor formation (Zeisberg, M et al 2005). The tendency of disseminated cancer cells to undergo EMT likely reflects the local microenvironments that they encounter after extravasation into the parenchyma of a distant organ, quite possibly the absence of the heterotypic signals they experienced in the primary tumor that were responsible for inducing the EMT in the first place (Thiery, J.P. 2002, Jechlinger, M et al 2002, Bissell, M.J et al 2002). These evidences indicate that induction of an EMT is likely to be a centrally important mechanism for the progression of carcinomas to a metastatic stage and implicates MET during the subsequent colonization process. However, many steps of this mechanistic model still require direct experimental validation. It remains unclear at present whether these phenomena and molecular mechanisms relate to and explain the metastatic dissemination of non-epithelial cancer cells.</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">The entire spectrum of signaling agents that contribute to EMTs of carcinoma cells remains unclear. One theory suggests that the genetic and epigenetic alterations undergone by cancer cells during the course of primary tumor formation render them especially responsive to EMT-inducing heterotypic signals originating in the tumor-associated stroma. Oncogenes induce senescence, and recent studies suggest that cancer cell EMTs may also play a role in preventing senescence induced by oncogenes, thereby facilitating subsequent aggressive dissemination (Smit, M.A., and Peeper, D.S. 2008, Ansieau, S., et al. 2008, Weinberg, R.A. 2008). In the case of many carcinomas, EMT-inducing signals emanating from the tumor-associated stroma, notably HGF, EGF, PDGF, and TGF-</span><span style="color:black">β</span><span style="color:black">, appear to be responsible for the induction or functional activation in cancer cells of a series of EMT-inducing transcription factors, notably Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), Twist, Goosecoid, and FOXC2 (Thiery, J.P. 2002, Jechlinger, M et al 2002, Shi, Y., and Massague, J. 2003, Niessen, K., et al. 2008, Medici, D et al 2008, Kokudo, T., et al. 2008). Once expressed and activated, each of these transcription factors can act pleiotropically to choreograph the complex EMT program, more often than not with the help of other members of this cohort of transcription factors. The actual implementation by these cells of their EMT program depends on a series of intracellular signaling networks involving, among other signal- transducing proteins, ERK, MAPK, PI3K, Akt, Smads, RhoB, </span><span style="color:black">β</span><span style="color:black">-catenin, lymphoid enhancer binding factor (LEF), Ras, and c-Fos as well as cell surface proteins such as </span><span style="color:black">β</span><span style="color:black">4 integrins, </span><span style="color:black">α</span><span style="color:black">5</span><span style="color:black">β</span><span style="color:black">1 integrin, and </span><span style="color:black">α</span><span style="color:black">V</span><span style="color:black">β</span><span style="color:black">6 integrin (Tse, J.C., and Kalluri, R. 2007). Activation of EMT programs is also facilitated by the disruption of cell-cell adherens junctions and the cell-ECM adhesions mediated by integrins (Yang, J., and Weinberg, R.A. 2008, Weinberg, R.A. 2008, Gupta, P.B et al 2005, Yang, J et al 2006, Mani, S.A., et al. 2007, Mani, S.A., et al. 2008, Hartwell, K.A., et al. 2006, Taki, M et al 2006)..</span></span></span></p>
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<p>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).</p>
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<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Method/ measurement referenc</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Reliability</span></span></p>
<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Strength of evidence</span></span></p>
<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Assay fit for purpose</span></span></p>
<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Repeatability/ reproducibility</span></span></p>
<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Direct measure</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Human cell line</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">qRT-PCR,cell viability assay,</span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Western blotting,EdU incorporation assay</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">+</span></span></p>
</td>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Strong</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes</span></span></p>
</td>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Human</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">IHC,micro array,qPCR, SNP array</span></span></p>
</td>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">+</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Moderate</span></span></p>
</td>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Regulation of miRNA expression by DNA replication,damage and repair responses,transcription and translation has been proved in animals like mice,canine and cell line experiments.</span></span></p>
Not SpecifiedUnspecificNot SpecifiedNot Otherwise SpecifiedHigh<p>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. <em>Thorax</em>, <em>64</em>(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133"><u>https://doi.org/10.1136/thx.2008.104133</u></a></p>
<p>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. <em>American Journal of Transplantation</em>, <em>10</em>(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x"><u>https://doi.org/10.1111/j.1600-6143.2009.02953.x</u></a></p>
<p>Al Saleh, S., Al Mulla, F., & Luqmani, Y. A. (2011). Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. PloS one, 6(6), e20610.</p>
<p>Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M., & Petersen, O. W. (2002). The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation, 70(9-10), 537-546.</p>
<p>Bouris, P., Skandalis, S. S., Piperigkou, Z., Afratis, N., Karamanou, K., Aletras, A. J., ... & Karamanos, N. K. (2015). Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biology, 43, 42-60.</p>
<p> Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361.</p>
<p>Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361.</p>
<p>idler, I. J., & Poste, G. (2008). The “seed and soil” hypothesis revisited. The lancet oncology, 9(8), 808.</p>
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<p>Jechlinger, M., Grünert, S., & Beug, H. (2002). Mechanisms in epithelial plasticity and metastasis: insights from 3D cultures and expression profiling. Journal of mammary gland biology and neoplasia, 7(4), 415-432.</p>
<p> Kalluri, R., & Neilson, E. G. (2003). Epithelial-mesenchymal transition and its implications for fibrosis. The Journal of clinical investigation, 112(12), 1776-1784.</p>
<p>Kokudo, T., Suzuki, Y., Yoshimatsu, Y., Yamazaki, T., Watabe, T., & Miyazono, K. (2008). Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. Journal of cell science, 121(20), 3317-3324.<br />
Lin, H. Y., Liang, Y. K., Dou, X. W., Chen, C. F., Wei, X. L., Zeng, D., ... & Zhang, G. J. (2018). Notch3 inhibits epithelial–mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression. Oncogenesis, 7(8), 1-15.</p>
<p>Liu, Y., Liu, R., Fu, P., Du, F., Hong, Y., Yao, M., ... & Zheng, S. (2015). N1-Guanyl-1, 7-diaminoheptane sensitizes estrogen receptor negative breast cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation. Cellular Physiology and Biochemistry, 36(6), 2494-2503.</p>
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<p>Thiery, J. P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature reviews cancer, 2(6), 442-454.</p>
<p>Tse, J. C., & Kalluri, R. (2007). Mechanisms of metastasis: epithelial‐to‐mesenchymal transition and contribution of tumor microenvironment. Journal of cellular biochemistry, 101(4), 816-829.</p>
<p>Weinberg, R. A. (2008). Twisted epithelial–mesenchymal transition blocks senescence. Nature cell biology, 10(9), 1021-1023.</p>
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<li><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="background-color:white"><span style="font-family:"Arial",sans-serif"><span style="color:#222222">Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. <em>Journal of proteomics</em>, <em>103</em>, 153-169.</span></span></span></span> </span></span></li>
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2017-07-26T19:11:332023-08-27T07:39:03Fibroproliferative airway lesionsFibroproliferative airway lesionsTissue<p>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).</p>
<p>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)</p>
<p>Flake, G. P., & Morgan, D. L. (2017). Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. <em>Toxicology</em>, <em>388</em>, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013"><u>https://doi.org/10.1016/j.tox.2016.10.013</u></a></p>
<p>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. <em>Toxicologic Pathology</em>, <em>44</em>(5), 763–783. https://doi.org/10.1177/0192623316638962</p>
2019-01-30T09:44:242019-01-30T10:28:20Bronchiolitis obliteransBronchiolitis obliteransIndividual<p>Bronchiolitis obliterans is a lung disease characterized by obstruction of the smallest airways of the lungs.</p>
<p>The cumulative exposure to DA correlated with the degree of airway obstruction and the incidence of BO (Kreiss et al. 2002).</p>
<p>Forced expiratory volume in 1 second (FEV1)</p>
<p>CT scan</p>
<p>Thoracoscopic lung biopsy showing histological and morphological changes (human, King et al. 2011)</p>
<p>Other typical symptoms include: dry cough, shortness of breath and wheezing.</p>
<p>Kreiss et al. 2002 (first report of DA induced BO)</p>
<p>Kreiss 2014 (changes in the human lung after DA exposure)</p>
2019-01-30T09:45:132019-01-30T10:28:554e0d23bd-6329-475f-9d12-5efcb63814f0ba8b39ac-9659-4758-8c34-c49f78f79b0d<p>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.</p>
<p>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.</p>
<p>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).</p>
<p>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.</p>
<p>Harden, A., Norris, D.,1911. The diacetyl reaction for proteins. J. Physiol. 42, 332–336.</p>
<p>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 <em>American Journal of Pathology</em> (Vol. 186, pp. 2887–2908). <a href="https://doi.org/10.1016/j.ajpath.2016.07.018"><u>https://doi.org/10.1016/j.ajpath.2016.07.018</u></a></p>
<p>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. <em>Journal of Agricultural and Food Chemistry</em>, <em>58</em>(24), 12761–12768. <a href="https://doi.org/10.1021/jf103251w"><u>https://doi.org/10.1021/jf103251w</u></a></p>
<p>Anders, M. W. (2017). Diacetyl and related flavorant α-Diketones: Biotransformation, cellular interactions, and respiratory-tract toxicity. <em>Toxicology</em>, <em>388</em>, 21–29. <a href="https://doi.org/10.1016/j.tox.2017.02.002"><u>https://doi.org/10.1016/j.tox.2017.02.002</u></a></p>
<p>Chen, G., Chen, X., 2003. Arginine residues in the active site of human phenol sulfotransferase (SULT1A1). J. Biol. Chem. 278, 36358–36364.</p>
<p>Ahmed, N., and Thomalley, P. J. (2003). Quantitative screening of protein biomarkers of early glycation, advanced glycation, oxidation and nitrosation of cellular and extracellular proteins by mass spectrometry multiple reaction monitoring. Biochem Soc Trans 31, 1417–22.</p>
<p>Xia, C., et al., 1993. Chemical modification of GSH transferase P 1-1 confirms the presence of Arg-13, Lys-44 and one carboxylate group in the GSH-binding domain of the active site. Biochem. J. 293, 357–362.</p>
<p>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.</p>
<p>Dorado, L., et al., 1992. A contribution to the study of the structure-mutagenicity relationship for a-dicarbonyl compounds using the Ames test. Mutat. Res. Fundam. Mol. Mech. Mutagen. 269, 301–306.</p>
2019-01-30T09:45:342019-01-30T10:41:36ba8b39ac-9659-4758-8c34-c49f78f79b0d23133bb0-1d7f-4292-8f72-1982dd120b07<p>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.</p>
<p>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.</p>
<p>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 <em>in vitro</em> models of airway epithelium to α-diketones leads to a complete destruction of the epithelial layer (Zaccone et al. 2015, Foster et al. 2017).</p>
<p>At present the sensitivity of the individual cell types of the airway epithelium upon exposure to α-diketones is largely unknown.</p>
<p>Hubbs, A. F., Cumpston, A. M., Goldsmith, W. T., Battelli, L. A., Kashon, M.</p>
<p>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.</p>
<p>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. <em>Journal of Proteome Research</em>, <em>16</em>(2), 538–549. <a href="https://doi.org/10.1021/acs.jproteome.6b00672"><u>https://doi.org/10.1021/acs.jproteome.6b00672</u></a></p>
<p>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 </p>
<p>obliterans after sulfur mustard inhalation injury in rats. <em>Toxicological Sciences</em>, <em>157</em>(2), 399–409. <a href="https://doi.org/10.1093/toxsci/kfx057"><u>https://doi.org/10.1093/toxsci/kfx057</u></a></p>
<p>Morgan, D. L., Jokinen, M. P., Johnson, C. L., Gwinn, W. M., Price, H. C., and</p>
<p>Flake, G. P. (2012). Bronchial fibrosis in rats exposed to 2,3-butanedione</p>
<p>and 2,3-pentanedione vapors. Toxicologist 126, 200.</p>
<p>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. <em>Toxicologic Pathology</em>, <em>44</em>(5), 763–783. <a href="https://doi.org/10.1177/0192623316638962"><u>https://doi.org/10.1177/0192623316638962</u></a></p>
<p>Flake, G. P., & Morgan, D. L. (2017). Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. <em>Toxicology</em>, <em>388</em>, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013"><u>https://doi.org/10.1016/j.tox.2016.10.013</u></a></p>
<p>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. <em>Toxicology and Applied Pharmacology</em>, <em>289</em>, 542–549. <a href="https://doi.org/10.1016/j.taap.2015.10.004"><u>https://doi.org/10.1016/j.taap.2015.10.004</u></a></p>
2019-01-30T09:45:512019-01-30T10:42:5323133bb0-1d7f-4292-8f72-1982dd120b0745ace960-3787-43b0-b3ec-9a1a71bfcacb<p>Damage of the airway epithelium leads to inflammatory reactions.</p>
<p>Inflammation is a biological response to harmful stimuli, including cell damage. Therefore, damage to airway epithelium will initiate inflammatory reactions.</p>
<p>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.</p>
<p>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.</p>
<p>Anderson, S.E., Jackson, L.G., Franko, J., Wells, J.R., 2010. Evaluation of dicarbonyls generated in a simulated indoor air environment using an in vitro exposure system. Toxicol. Sci. 115, 453–461.</p>
<p>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. <em>Toxicological Sciences</em>, <em>157</em>(2), 399–409. <a href="https://doi.org/10.1093/toxsci/kfx057"><u>https://doi.org/10.1093/toxsci/kfx057</u></a></p>
2019-01-30T09:46:102019-01-30T10:43:4245ace960-3787-43b0-b3ec-9a1a71bfcacb98e72bf8-3b17-4c08-ad2f-d5f13a40f541<p>The inflammatory reactions initiated by the damaged airway epithelium might stimulate the transition of fibroblasts present in the underlying mesenchymal tissue to myofibroblasts.</p>
<p>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.</p>
<p>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).</p>
<p>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.</p>
<p>Ramirez, A. M., Shen, Z., Ritzenthaler, J. D., & Roman, J. (2006). Myofibroblast Transdifferentiation in Obliterative Bronchiolitis: TGF-β Signaling Through Smad3-Dependent and -Independent Pathways. <em>American Journal of Transplantation</em>, <em>6</em>(9), 2080–2088. <a href="https://doi.org/10.1111/j.1600-6143.2006.01430.x"><u>https://doi.org/10.1111/j.1600-6143.2006.01430.x</u></a></p>
2018-03-18T09:50:092019-01-30T10:58:4845ace960-3787-43b0-b3ec-9a1a71bfcacb947ae3cc-6f04-4944-89d7-787d36f74ff4<p>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.</p>
<p>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.</p>
<p>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).</p>
<p>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.</p>
<p>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. <em>Toxicologic Pathology</em>, <em>44</em>(5), 763–783. <a href="https://doi.org/10.1177/0192623316638962"><u>https://doi.org/10.1177/0192623316638962</u></a></p>
<p>Flake, G. P., & Morgan, D. L. (2017). Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. <em>Toxicology</em>, <em>388</em>, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013"><u>https://doi.org/10.1016/j.tox.2016.10.013</u></a></p>
<p>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. <em>Toxicological Sciences</em>, <em>157</em>(2), 399–409. <a href="https://doi.org/10.1093/toxsci/kfx057"><u>https://doi.org/10.1093/toxsci/kfx057</u></a></p>
2019-01-30T09:46:432019-01-30T10:57:1098e72bf8-3b17-4c08-ad2f-d5f13a40f541947ae3cc-6f04-4944-89d7-787d36f74ff4<p>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.</p>
<p>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.</p>
<p>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).</p>
<p>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.</p>
<p>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. <em>Toxicologic Pathology</em>, <em>44</em>(5), 763–783. <a href="https://doi.org/10.1177/0192623316638962"><u>https://doi.org/10.1177/0192623316638962</u></a></p>
<p>Flake, G. P., & Morgan, D. L. (2017). Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. <em>Toxicology</em>, <em>388</em>, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013"><u>https://doi.org/10.1016/j.tox.2016.10.013</u></a></p>
<p>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. <em>Toxicological Sciences</em>, <em>157</em>(2), 399–409. <a href="https://doi.org/10.1093/toxsci/kfx057"><u>https://doi.org/10.1093/toxsci/kfx057</u></a></p>
2019-01-30T09:57:472019-01-30T10:59:39947ae3cc-6f04-4944-89d7-787d36f74ff4a3c65abc-d2b7-4c7a-b754-23fdfec1bd4d<p>Excessive proliferation of fibrotic cells and the deposition of extracellular matrix leads to the occlusion of the lumen of the smaller airways.</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
<p>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. <em>Toxicologic Pathology</em>, <em>44</em>(5), 763–783. <a href="https://doi.org/10.1177/0192623316638962"><u>https://doi.org/10.1177/0192623316638962</u></a></p>
<p>Rose, C. S. (2017). Early detection, clinical diagnosis, and management of lung disease from exposure to diacetyl. <em>Toxicology</em>, <em>388</em>, 9–14. <a href="https://doi.org/10.1016/j.tox.2017.03.019"><u>https://doi.org/10.1016/j.tox.2017.03.019</u></a></p>
2019-01-30T10:00:082019-01-30T11:01:08α-diketone-induced bronchiolitis obliteransα-diketone-induced bronchiolitis obliterans<p>Jan Boeij, Harry Vrielingh, Pieter Hiemstra, Inga Tluczkiewicz</p>
Under development: Not open for comment. Do not cite<p>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.</p>
<p>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.</p>
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