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Activation, EGFR leads to Decrease, Apoptosis of ciliated epithelial cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|EGFR Activation Leading to Decreased Lung Function||adjacent||Moderate||Low||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Exogenous oxidative stress arising from e.g. the exposure to airborne toxicants and pathogens as well as oxidative stress induced by inflammatory responses mediate proteolytic cleavage of membrane-bound EGFR ligand precursors (Burgel and Nadel, 2004; Gao et al., 2015; Øvrevik et al., 2015). Subsequent ligand binding then activates the receptor tyrosine kinase in an autocrine fashion. Downstream of EGFR activation, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling elicits an anti-apoptotic response in ciliated cells favoring their survival (Tyner et al., 2006).
Evidence Supporting this KER
Tyner et al. (2006) reported that ciliated cell survival in a mouse airway infection model is promoted via EGFR-dependent PI3K/Akt signaling. Other studies provide indirect support of a variety of stressors known to activate EGFR causing apoptosis of airway epithelial cells, although the identity of cells is not always specified (Casalino-Matsuda et al., 2006; Tesfaigzi et al., 2000; Tesfaigzi et al., 1998; Song et al., 2016; Sydlik et al., 2006).
Downstream EGFR signaling involving the PI3K/AKT pathway regulating cell survival is well-documented, in particular in cancer cells where this pathway is often deregulated (e.g. Hennessey et al., 2005). However, to date, very few studies reported on the direct link between EGFR activation and the identity of airway epithelial cells undergoing apoptosis, so biological plausibility is only moderate.
Uncertainties and Inconsistencies
Some evidence available to date is correlative, demonstrating increased ciliated cell numbers following EGFR or EGFR/PI3K blockade. Other studies make no reference to the airway epithelial cell type that is affected by apoptosis.
EGFR was persistently activated in ciliated cells C57Bl/6J mouse lungs at day 21, but not day 12, post-inoculation with Sendai virus, which coincided with an increased number of ciliated cells but not with proliferation markers BrdU, Ki67 or PCNA (Tyner et al., 2006).
In rat alevolar epithelial cells, treatment with ultrafine caron black particles results in phosphorylation of EGFR after 2 minutes and a second, more persistent activation of the receptor from 120 to 480 minutes. Caspase 3 activity increases in a time-dependent manner, starting at 4 hours and reaching a maximum after 8 hours (Sydlik et al., 2006).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The studies that support epithelial cell apoptosis induced by EGFR include rat, mouse and human in vitro experiments.
Burgel, P., and Nadel, J. (2004). Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 59, 992-996.
Casalino-Matsuda, S., Monzón, M., and Forteza, R. (2006). Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium. Am J Respir Cell Mol Biol 34, 581–591.
Curran, D., and Cohn, L. (2010). Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am J Respir Cell Mol Biol 42, 268–275.
Gao, W., Li, L., Wang, Y., Zhang, S., Adcock, I.M., Barnes, P.J., Huang, M., and Yao, X. (2015). Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease? Respirology 20, 722-729.
Hennessy, B.T., Smith, D.L., Ram, P.T., Lu, Y. and Mills, G.B., 2005. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4, 988-1004.
Øvrevik, J., Refsnes, M., Låg, M., Holme, J.A., and Schwarze, P.E. (2015). Activation of proinflammatory responses in cells of the airway mucosa by particulate matter: Oxidant- and non-oxidant-mediated triggering mechanisms. Biomolecules 5, 1399-1440.
Sydlik, U., Bierhals, K., Soufi, M., Abel, J., Schins, R.P.F., and Unfried, K. (2006). Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R. Am J Physiol Lung Cell Mol Physiol 291, L725–L733.
Tesfaigzi, J., Hotchkiss, J.A., and Harkema, J.R. (1998). Expression of the Bcl-2 protein in nasal epithelia of F344/N rats during mucous cell metaplasia and remodeling. Am J Resp Cell Mol Biol 18, 794-799.
Tesfaigzi, Y., Fischer, M.J., Martin, A.J., and Seagrave, J. (2000). Bcl-2 in LPS- and allergen-induced hyperplastic mucous cells in airway epithelia of Brown Norway rats. Am J Physiol Lung Cell Mol Physiol 279, L1210-L1217.
Tyner, J., Tyner, E., Ide, K., Pelletier, M., Roswit, W., Morton, J., Battaile, J., Patel, A., Patterson, G., Castro, M., et al. (2006). Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. J Clin Invest 116, 309–321.