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Relationship: 962


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, EGFR leads to Decreased ciliated cell apoptosis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Karsta Luettich (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Low

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Exposure to airborne toxicants and pathogens causing oxidative stress as well as oxidative stress induced by inflammatory responses to environmental exposures 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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Tyner et al. (2006) reported that ciliated cell survival in a mouse airway infection model is promoted via EGFR-dependent PI3K/Akt signaling. Oxidative stress following inhalation exposure increased Bcl-2 mRNA and protein levels in human and rat airway epithelial cells (Casalino-Matsuda et al., 2006; Foster et al., 2003; Lee et al., 2011; Tesfaigzi et al., 1998; Tesfaigzi et al., 2000; Petecchia et al., 2009). Neutralization of Bcl-2 expression in rat nasal epithelium reduced goblet cell metaplasia (Harris et al., 2005), and treatment of OVA-sensitized Balb/c mice with the EGFR inhibitor gefitinib decreased Bcl-2 expression and increased apoptosis (Song et al., 2016).

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Some evidence available to date is correlative, demonstrating increased ciliated cell numbers following EGFR or EGFR/PI3K blockade. Other studies provide indirect support of a variety of stressors known to activate EGFR causing apoptosis of airway epithelial cells, although the identity of the affected cells is not always specified (Tesfaigzi et al., 2000; Tesfaigzi et al., 1998; Song et al., 2016; Sydlik et al., 2006). Other studies make no reference to the airway epithelial cell type that is affected by apoptosis. 

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help


Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

In primary bronchial epithelial cells, treatment with 0.6 mM xanthine and 0.05 units xanthine oxidase (X/XO) for 30 min doubled the pEGFR/EGFR ratio and increased the Bcl-2/actin mRNA ratio by ca. 5-fold. Both effects could be at least partially suppressed by pretreatment of cells with anti-EGFR neutralizing antibodies. Of note, this study was focused on goblet cells; however, the described mechanism may also apply to ciliated cells (Casalino-Matsuda et al., 2006).

Sendai virus, delivered at 2 × 105 PFUs intranasally to C57Bl/6J mice, caused EGFR activation (not quantified) in ciliated cells 21 days after inoculation, which was accompanied by an approx. 40-fold increase in ciliated cell number in the absence of proliferation as evidenced by the lack of BrdU staining. Complementary experiments in mouse tracheal epithelial cells grown at the air-liquid interface stimulated with 1 or 10 ng/mL EGF also demonstrated EGFR activation (not quantified), and EGFR blockade with PD153035 caused a dose-dependent decrease in ciliated cell numbers, with a maximum decrease (50%) seen at 0.3 µM inhibitor, while the number of TUNEL- and caspase 3-positive cells nearly tripled and quadrupled, respectively (Tyner et al., 2006).

EGFR phosphorylation was increased approx. 3-fold in rat alveolar epithelial cells (RLE-6TN) exposed to 10 µg/cm2 ultrafine carbon black particles for as little as 2 min. After an 8-h exposure, DNA fragmentation had doubled and caspase 3 activity tripled, but the latter could be almost completely suppressed by pretreatment with the EGFR inhibitor AG1478 (Sydlik et al., 2006).

Treatment of NCI-H292 lung cancer cells with 10 ng/mL the EGFR ligand TGFa for 24 h increased Bcl-2 protein expression by 50%, which was prevented by pretreatment with AG1478 (Takeyama et al., 2008).

Treatment of immortalized human bronchial epithelial BEAS-2B cells with 0.1 mM Ni2+ for 24 h significantly increased EGFR mRNA expression (1.59 ± 0.04-fold compared to untreated), EGFR phosphorylation and Bcl-2 protein expression levels (Giunta et al., 2012).

Treatment of primary human airway epithelial cells, grown as a monolayer, with 10 µg/mL cigarette smoke extract for 48 h increased EGFR phosphorylation by approx. 50%, Bcl-2 mRNA expression ca. 2.5-fold and Bcl-2 protein expression ca. 4.5-fold (Hussain et al., 2018).

In the small airways of male Sprague-Dawley rats that were exposed to cigarette smoke generated from 5 unfiltered cigarettes for 30 min twice daily for 4 weeks, the rate of apoptosis, as assessed by TUNEL staining, increased by 50%, and phosphorylation of EGFR at Tyr1068 increased 5.1-fold  (Ning et al., 2013).

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

EGFR was persistently activated in ciliated cells in 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 (approx. 10% increase in ß-tubulin-positive cells), a decreased number of goblet cells (approx. 10% decrease in Muc5ac-positive cells), but not with the expression of the proliferation markers BrdU, Ki67 or PCNA (Tyner et al., 2006).

In rat alevolar epithelial cells, treatment with ultrafine carbon black particles resulted in phosphorylation of EGFR after 2 minutes and a second, more persistent activation of the receptor from 120 to 480 min. Caspase 3 activity increased in a time-dependent manner, starting at 4 h and reaching a maximum after 8 h (Sydlik et al., 2006).

Intranasal influenza virus infection (7.5 PFU of H1N1) led to the loss of ciliated epithelial cells (acetylated tubulin–positive) by day 3, with recovery of the epithelial barrier by day 14 (Fujino et al., 2019). EGFR promotes uptake of influenza viruses and is activated (ca. 2-fold increase in phosphorylated EGFR) at 10 min following infection of immortalized human bronchial epithelial BEAS-2B cells (Ueki et al., 2013).

Chronic, 6-month exposure of immortalized human bronchial epithelial BEAS-2B cells to 0.25 μm Cr(VI) activated EGFR constitutively, beginning from month 2, and permanently elevated Bcl-2 protein levels (Kim et al., 2015).

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help


Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The studies that support epithelial cell apoptosis induced by EGFR activation include rat and mouse in vivo experiments and in vitro experiments in human and rat cells.


List of the literature that was cited for this KER description. More help

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.

Fujino, N., Brand, O.J., Morgan, D.J., Fujimori, T., Grabiec, A.M., Jagger, C.P., et al. (2019). Sensing of apoptotic cells through Axl causes lung basal cell proliferation in inflammatory diseases. J. Exp. Med. 216, 2184-2201.

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? Respirol. 20, 722-729.

Giunta, S., Castorina, A., Scuderi, S., Patti, C., and D’agata, V. (2012). Epidermal growth factor receptor (EGFR) and neuregulin (Neu) activation in human airway epithelial cells exposed to nickel acetate. Toxicol. In Vitro 26, 280-287.

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.

Hussain, S.S., George, S., Singh, S., Jayant, R., Hu, C.-A., Sopori, M., et al. (2018). A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells. Sci. Rep. 8(1), 13796-13796. 

Kim, D., Dai, J., Fai, L.Y., Yao, H., Son, Y.-O., Wang, L., et al. (2015). Constitutive activation of epidermal growth factor receptor promotes tumorigenesis of Cr(VI)-transformed cells through decreased reactive oxygen species and apoptosis resistance development. J. Biol. Chem. 290, 2213-2224. 

Ning, Y., Shang, Y., Huang, H., Zhang, J., Dong, Y., Xu, W., et al. (2013). Attenuation of cigarette smoke-induced airway mucus production by hydrogen-rich saline in rats. PLoS One 8, e83429.

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.

Petecchia, L., Sabatini, F., Varesio, L., Camoirano, A., Usai, C., Pezzolo, A., et al. (2009). Bronchial airway epithelial cell damage following exposure to cigarette smoke includes disassembly of tight junction components mediated by the extracellular signal-regulated kinase 1/2 pathway. Chest 135, 1502-1512. 

Song, L., Tang, H., Liu, D., Song, J., Wu, Y., Qu, S., et al. (2016). The chronic and short-term effects of gefinitib on airway remodeling and inflammation in a mouse model of asthma. Cell. Physiol. Biochem. 38, 194-206.

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.

Ueki, I.F., Min-Oo, G., Kalinowski, A., Ballon-Landa, E., Lanier, L.L., Nadel, J.A., et al. (2013). Respiratory virus-induced EGFR activation suppresses IRF1-dependent interferon λ and antiviral defense in airway epithelium. J. Exp. Med. 210, 1929-1936.