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Event: 941

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Activation, EGFR

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help

Activation, EGFR

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Level of Biological Organization
Molecular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. More help

Cell term
epithelial cell

Organ term

Organ term
lung

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Process	Object	Action
epidermal growth factor-activated receptor activity	epidermal growth factor receptor	occurrence
phosphorylation	epidermal growth factor receptor	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Decreased lung function	MolecularInitiatingEvent	Cataia Ives (send email)	Under development: Not open for comment. Do not cite	Under Development

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Name
Cigarette smoke
Acrolein
Hydrogen peroxide
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
Nicotine
benzo[a]pyrene
PM 2.5
Wood smoke
2,3-Butanedione
Carbon nanotubes
Ozone
1,2,5,6,9,10-Hexabromocyclododecane
Tetrabromobisphenol A

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Life stage	Evidence
Adult	High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Term	Evidence
Mixed	Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

The EGF receptor family comprises 4 members, EGFR (also referred to as ErbB1/HER1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4, all of which are transmembrane glycoproteins with an extracellular ligand binding site and an intracellular tyrosine kinase domain. Receptor-ligand binding induces dimerization and internalization, subsequently leading to activation of the receptor through autophosphorylation (Higashiyama et al., 2008).

EGFR signaling is central to airway epithelial maintenance and mucin production (Burgel and Nadel, 2004), and EGFR expression has been demonstrated in lung epithelial cells under physiological (albeit weakly) as well as pathological conditions in vitro and in vivo (Aida et al., 1994; Burgel and Nadel, 2008; O’Donnell et al., 2004; Polosa et al., 1999). Of note, lung epithelial cell EGFR phosphorylation (i.e., activation) was increased under conditions of oxidative stress including exposure to H₂O₂ (Goldkorn et al., 1998), naphthalene (Van Winkle et al., 1997), cigarette smoke (de Boer et al., 2006; Marinaş et al., 2011) and in the presence of neutrophils or neutrophil elastase (Kohri et al., 2002; Shao et al., 2004; Shao and Nadel, 2005; Shim et al., 2001; Takeyama et al., 2000). EGFR activation by oxidative stress may have a number of root causes: ROS were shown to increase production of EGF, the prime EGFR ligand, by lung epithelial cells (Casalino-Matsuda et al., 2004). Similarly, expression and secretion of TGF-α and AREG, also EGFR ligands, were elevated in human bronchial epithelial cells in response to fine particulate matter (PM2.5), diesel particulate matter and cigarette smoke exposure (Blanchet et al., 2004; Lemjabbar et al., 2003; Rumelhard et al., 2007). Mechanistically, this process is dependent on ROS-mediated activation of metalloproteinases or ADAMs which cleave membrane-bound EGFR ligand precursors, making them locally available to bind to and transactivate EGFR in an autocrine manner (Deshmukh et al., 2009; Kim et al., 2004b; Val et al., 2012; Yoshisue and Hasegawa, 2004). Furthermore, ligand binding to EGFR itself was shown to lead to H₂O₂ production, thereby facilitating receptor activation and downstream signaling (DeYulia et al., 2005; DeYulia and Cárcamo, 2005; Truong and Carroll, 2012). While it is tempting to speculate that the increase in H₂O₂ would perpetuate EGFR activation via the continuous proteolytic shedding of pro-ligands in an autocrine loop, multiple lines of evidence suggest that oxidative modification, specifically EGFR sulfenylation, contributes to enhanced tyrosine phosphorylation of the receptor and downstream signaling (Paulsen et al., 2011; Ravid et al., 2002; Truong and Carroll, 2012; Truong et al., 2016).

Classical EGFR downstream signaling involves activation of Ras which subsequently initiates signal transduction through the Raf-1/MEK/ERK pathway. MAP kinase activation in turn promotes airway epithelial cell proliferation and differentiation (Hackel et al., 1999; Kim et al., 2005; Lemjabbar et al., 2003) and facilitates epithelial wound repair (Allahverdian et al., 2010; Burgel and Nadel, 2004; Van Winkle et al., 1997).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Proof of EGFR activation can be derived from Western blots of e.g. untreated and treated cell or tissue lysates using specific antibodies targeting the phosphorylated EGFR epitopes. Densitometric evaluation of the colorimetrically stained, chemiluminescent or radioactive bands on the blot then permit a (semi-)quantitative measure of activation. Moreover, the addition of EGFR inhibitors such as AG1478 and BIBX 1522 or neutralizing antibodies is well suited to demonstrate causality.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information. More help

EGFR activation in human, mouse and rat is well documented, and EGF ligands and EGFR are orthologous in these species. EGFR is a driver of human cancer in various tissues and numerous drugs are approved that inhibit EGFR activation (Ciardiello and Tortora, 2008). Although EGFR and its ligands are expressed in human, mouse and rat, species differences have been noted in binding and structure (Nexø and Hansen, 1985), and even can have opposite downstream effects in mouse and rat (Kiley and Chevalier, 2007).

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

EGFR activation in lung epithelial cells can be triggered by exposure to H₂O₂ (Goldkorn et al., 1998; Takeyama et al., 2000), naphthalene (Van Winkle et al., 1997), cigarette smoke (Takeyama et al., 2001; de Boer et al., 2006; Marinaş et al., 2011; Yu et al., 2011; Yu et al., 2015), acrolein (Deshmukh et al., 2008), and TCDD (Lee et al., 2011). Mechanistically, this process is dependent on ROS-mediated activation of metalloproteinases or ADAMs which cleave membrane-bound EGFR ligand precursors, making them locally available to bind to and transactivate EGFR in an autocrine manner (Deshmukh et al., 2009; Kim et al., 2004; Val et al., 2012; Yoshisue and Hasegawa, 2004). Furthermore, ligand binding to EGFR itself was shown to lead to H₂O₂ production, thereby facilitating receptor activation and downstream signaling (DeYulia et al., 2005; DeYulia and Cárcamo, 2005; Truong and Carroll, 2012).

Cigarette smoke

EGFR phosphorylation increased in lungs of Sprague-Dawley rats that were whole-body exposed (inExpose smoking system; SCIREQ, Montreal, Canada) at a total particulate matter (TPM) concentration of 2000 mg/m³ for 1 h (20 cigarettes) daily for 56 days (Chen et al., 2020); in lungs of Sprague-Dawley rats exposed to 12 cigarettes daily for 40 days (Nie et al., 2012); inlungs of Sprague-Dawley rats that were whole body-exposed to six nonfiltered cigarettes per day, 5 d/wk, for 2 to 28 days (Hegab et al., 2007); in lungs of Sprague-Dawley rats exposed to 10 cigarettes per h, 6 h per day for 60 days (Wu et al., 2011); in lungs of C57Bl6/J mice exposed to cigarette smoke at a TPM concentration of 100 mg/m³(Teague Enterprises, Davis, CA) for 6 h a day, 5 days a week for two weeks (Mishra et al., 2016); in lungs of A/J mice that were exposed to cigarette smoke at a TPM concentration of 80 mg/m³ (Teague Enterprises, Davis, CA) for 4 h a day, 5 days per week for 1 year (Geraghty et al., 2014); in lungs of Balb/c mice exposed to mainstream cigarette smoke for 2 h twice daily, 6 days per week for 4 weeks (Wang et al., 2018); in primary human bronchial epithelial cells and NuLi-1 bronchial epithelial cell monolayers following exposure to cigarette smoke (Mishra et al., 2016); in primary bronchial epithelial cell monolayers following treatment with cigarette smoke extract (Zhang et al., 2012); in primary human airway epithelial cells differentiated at the air-liquid interface following treatment with cigarette smoke extract (Zhang et al., 2013; Hussain et al., 2018; Cortijo et al., 2011; Chen et al., 2010) or exposure to whole mainstream cigarette smoke (Amatngalim et al., 2016); in human small airway epithelial cell monolayers following treatment with cigarette smoke extract (Geraghty et al., 2014; Agraval and Yadav, 2019); in human NCI-H292 lung cancer cells following treatment with cigarette smoke extract (Takeyama et al., 2001; Shao et al., 2004; Lee et al., 2006; Yang et al., 2012; Wang et al., 2018); in human A549 lung cancer cells following treatment with cigarette smoke extract for 15 min (Dey et al., 2011) or 3 h (Agraval and Yadav, 2019); in immortalized human bronchial epithelial 1HAEo cells following exposure to cigarette smoke (Zhang et al., 2005); human immortalized 16HBE bronchial epithelial cells following treatment with 10% cigarette smoke extract for 24 h (Yu et al., 2015) or 5% cigarette smoke extract for up to 6 h (Heihjink et al., 2012); A549 lung adenocarcinoma and HBE1 papilloma virus-immortalized human bronchial epithelial cells following exposure to cigarette smoke (Khan et al., 2008).

EGFR phosphorylation was approx. two-fold higher in lung tissues, alveolar type II and bronchial epithelial cells of healthy smokers compared to non-smokers and was also elevated in the lungs and lung epithelial cells of COPD smokers (Mishra et al., 2016).

Acrolein

EGFR activation was seen in human NCI-H292 lung cancer cells following treatment with 0.03 µM acrolein for 1 h (Deshmukh et al., 2005; Deshmukh et al., 2008).

Treatment of human normal oral keratinocytes with 5 µM acrolein for 3 h also increased EGFR phosphorylation (Tsou et al., 2021).

Hydrogen peroxide

H₂O₂ treatment increased EGFR tyrosine phosphorylation in NCI-H292 lung cancer cells (Takeyama et al., 2000) and in normal human nasal epithelial cells (Kim et al., 2008; Kim et al., 2010).

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Phosphorylation of EGFR was significantly increased in normal human bronchial epithelial cells differentiated at the air-liquid interface following treatment with 10 nM TCDD for 0.5, 3, 4, and 6 h (Lee et al., 2011).

Nicotine

Increased EGFR phosphorylation was seen in normal human bronchial epithelial cells following treatment with 500 μM nicotine for 1 h (Martínez-García et al., 2008) or with 1 nM nicotine for 48 h (Lupacchini et al., 2021). EGFR activation is also seen in human lung cancer cells (A549, H1975) following treatment with 100 nM nicotine (Wang et al., 2020), human dysplastic oral keratinocytes following treatment with up to 10 µM nicotine (Wisniewski et al., 2018).

benzo[a]pyrene

EGFR phosphorylation increased in A549 lung cancer cells treated with 1 µM benzo[a]pyrene for 4 or 2 weeks (Kometani et al., 2009).

Treatment of immortalized human bronchial epithelial HBEC-2 and BEAS-2B cells with BPDE for 2 h increased EGFR activation in a dose-dependent manner (Xu et al., 2012).

PM 2.5

Intratracheal instillation of PM 2.5 (collected at a major city of central China; 4 mg/kg body weight) in Balb/c mice once a day for 5 consecutive days induced phosphorylation of EGFR (Tyr1068) in lung tissues (Jin et al., 2016).

Intratracheal instillation of PM 2.5 (collected at Seoul, Korea), either as an aqueous extract or a dichloromethane extract at high concentrations (164 µg/50 µL), in Balb/c mice once a week for 4 weeks induced phosphorylation of EGFR (Tyr1068) in lung tissues (Jeong et al., 2017).

Treatment of human immortalized bronchial epithelial BEAS-2B cells with with 0, 20, 50, 100 and 150 μg/mL PM 2.5 (collected on the roof of Science and Technology Building on the campus of Xinxiang Medical University, China) for 6 h increased EGFR Y1068 phosphorylation in a concentration-dependent manner (Wang et al., 2020).

Wood smoke

EGFR activation (increased phospho-EGFR (Y1068)) was seen in primary human lobar bronchial epithelial cells incubated with 20 µg/cm² pine wood smoke particulate matter (WSPM) for 6 h, but not at 2 h (Memon et al., 2020).

In NCI-H292 lung cancer cells stimulated with WSPM2.5 (8 μg/mL), EGFR phosphorylation increased continuously over time, with a significant increase observed at 60 min (Huang et al., 2017).

2,3-Butanedione

EGFR phosphorylation increased in H292 lung cancer cells following treatment with diacetyl (2,3-butanedione) (Kelly et al., 2019).

Carbon nanotubes

Treatment of rat RLE-6TN lung epithelial cells with 10 µg/cm² carbon nanoparticles (CNP Printex 90, Degussa, Essen, Germany) for 5 min significantly increased EGFR Tyr845 phosphorylation (Stöckmann et al., 2018).

Ozone

Exposure to O₃ (0.25–1.0 ppm) concentration- and time-dependently increased EGFR Y1068 and Y845 phosphorylation in human immortalized bronchial epithelial BEAS-2B cells (Wu et al., 2015).

Exposure of Balb/c mice to 0.25, 0.5, or 1.0 ppm ozone for 3 h a day, for 7 days increased EGFR Y1068 phosphorylation in the bronchial epithelium in a concentration-dependent manner (Feng et al., 2016).

1,2,5,6,9,10-Hexabromocyclododecane

EGFR phosphorylation increased significantly in human immortalized bronchial epithelial BEAS-2B cells following exposure to 10 μg/mL hexabromocyclodecane for 15 min (Koike et al., 2016).

Tetrabromobisphenol A

EGFR phosphorylation increased significantly in human immortalized bronchial epithelial BEAS-2B cells following exposure to 10 μg/mL tetrabromobisphenol A for 15 min (Koike et al., 2016).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Agraval, H., and Yadav, U.C. (2019). MMP-2 and MMP-9 mediate cigarette smoke extract-induced epithelial-mesenchymal transition in airway epithelial cells via EGFR/Akt/GSK3β/β-catenin pathway: Amelioration by fisetin. Chem. Biol. Interact. 314, 108846.

Aida, S., Tamai, S., Sekiguchi, S., and Shimizu, N. (1994). Distribution of epidermal growth factor and epidermal growth factor receptor in human lung: immunohistochemical and immunoelectron-microscopic studies. Respiration 61, 161-166.

Allahverdian, S., Wang, A., Singhera, G.K., Wong, B.W., and Dorscheid, D.R. (2010). Sialyl Lewis X modification of the epidermal growth factor receptor regulates receptor function during airway epithelial wound repair. Clin. Exp. Allergy 40, 607-618.

Amatngalim, G.D., Broekman, W., Daniel, N.M., van der Vlugt, L.E., van Schadewijk, A., Taube, C., et al. (2016). Cigarette Smoke Modulates Repair and Innate Immunity following Injury to Airway Epithelial Cells. PLoS One 11, e0166255.

Blanchet, S., Ramgolam, K., Baulig, A., Marano, F., and Baeza-Squiban, A. (2004). Fine particulate matter induces amphiregulin secretion by bronchial epithelial cells. Am. J. Respir. Cell .Mol. Biol. 30, 421-427.

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.

Burgel, P.-R., and Nadel, J.A. (2008). Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur. Respir. J. 32, 1068-1081.

Casalino-Matsuda, S.M., Monzón, M.E., and Forteza, R.M. (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.

Chen, H., et al., Epidermal growth factor receptor in adult retinal neurons of rat, mouse, and human. J Comp Neurol 2007. 500(2):299-310.

Chen, R., Liang, Y., Ip, M.S.M., Zhang, K.Y., and Mak, J.C.W. (2020). Amelioration of Cigarette Smoke-Induced Mucus Hypersecretion and Viscosity by Dendrobium officinale Polysaccharides In Vitro and In Vivo. Oxid. Med. Cell Longev. 2020, 8217642-8217642.

Chen, Y.-T., Gallup, M., Nikulina, K., Lazarev, S., Zlock, L., Finkbeiner, W., et al. (2010). Cigarette smoke induces epidermal growth factor receptor-dependent redistribution of apical MUC1 and junctional beta-catenin in polarized human airway epithelial cells. Am. J. Pathol. 177, 1255-1264.

Ciardiello, F., and Tortora, G. (2008). EGFR antagonists in cancer treatment. N. Engl. J. Med. 358, 1160-1174.

Cortijo, J., Mata, M., Milara, J., Donet, E., Gavaldà, A., Miralpeix, M., et al. (2011). Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways. Eur. Respir. J. 37, 244-254.

de Boer, W.I., Hau, C.M., van Schadewijk, A., Stolk, J., van Krieken, J.H.J.M., and Hiemstra, P.S. (2006). Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease. Am. J. Clin. Pathol. 125, 184-192.

Deshmukh, H.S., Case, L.M., Wesselkamper, S.C., Borchers, M.T., Martin, L.D., Shertzer, H.G., et al. (2005). Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Am. J. Respir. Crit. Care Med. 171, 305-314.

Deshmukh, H.S., McLachlan, A., Atkinson, J.J., Hardie, W.D., Korfhagen, T.R., Dietsch, M., et al. (2009). Matrix metalloproteinase-14 mediates a phenotypic shift in the airways to increase mucin production. Am. J. Respir. Crit. Care Med. 180, 834-845.

Deshmukh, H.S., Shaver, C., Case, L.M., Dietsch, M., Wesselkamper, S.C., Hardie, W.D., et al. (2008). Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am. J. Respir. Cell Mol. Biol. 38, 446-454.

Dey, N., Chattopadhyay, D.J., and Chatterjee, I.B. (2011). Molecular mechanisms of cigarette smoke-induced proliferation of lung cells and prevention by vitamin C. J. Oncol. 2011, 561862.

DeYulia, G.J., Cárcamo, J.M., Bórquez-Ojeda, O., Shelton, C.C., and Golde, D.W. (2005). Hydrogen peroxide generated extracellularly by receptor–ligand interaction facilitates cell signaling. Proc. Nat. Acad. Sci. U. S. A. 102(14), 5044-5049.

DeYulia Jr., G.J., and Cárcamo, J.M. (2005). EGF receptor-ligand interaction generates extracellular hydrogen peroxide that inhibits EGFR-associated protein tyrosine phosphatases. Biochem. Biophys. Res. Comm. 334, 38-42.

Feng, F., Jin, Y., Duan, L., Yan, Z., Wang, S., Li, F., et al. (2016). Regulation of ozone-induced lung inflammation by the epidermal growth factor receptor in mice. Environ. Toxicol. 31, 2016-2027.

Geraghty, P., Hardigan, A., and Foronjy, R.F. (2014). Cigarette smoke activates the proto-oncogene c-src to promote airway inflammation and lung tissue destruction. Am. J. Respir. Cell Mol. Biol. 50, 559-570.

Goldkorn, T., Balaban, N., Matsukuma, K., Chea, V., Gould, R., Last, J., et al. (1998). EGF-receptor phosphorylation and signaling are targeted by H2O2 redox stress. Am. J. Respir. Cell Mol. Biol. 19, 786-798.

Hackel, P.O., Zwick, E., Prenzel, N., and Ullrich, A. (1999). Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr. Opin. Cell Biol. 11, 184-189.

Higashiyama, S., Iwabuki, H., Morimoto, C., Hieda, M., Inoue, H., and Matsushita, N. (2008). Membrane-anchored growth factors, the epidermal growth factor family: Beyond receptor ligands. Cancer Sci. 99, 214-220.

Huang, L., Pu, J., He, F., Liao, B., Hao, B., Hong, W., et al. (2017). Positive feedback of the amphiregulin-EGFR-ERK pathway mediates PM2.5 from wood smoke-induced MUC5AC expression in epithelial cells. Sci. Rep. 7, 11084.

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, 13796-13796.

Jeong, S.C., Cho, Y., Song, M.K., Lee, E., and Ryu, J.C. (2017). Epidermal growth factor receptor (EGFR)—MAPK—nuclear factor (NF)‐κB—IL8: A possible mechanism of particulate matter (PM) 2.5‐induced lung toxicity. Environ. Toxicol. 32, 1628-1636.

Jin, Y., Wu, W., Zhang, W., Zhao, Y., Wu, Y., Ge, G., et al. (2017). Involvement of EGF receptor signaling and NLRP12 inflammasome in fine particulate matter‐induced lung inflammation in mice. Environm. Toxicol. 32, 1121-1134.

Kelly, F.L., Weinberg, K.E., Nagler, A.E., Nixon, A.B., Star, M.D., Todd, J.L., et al. (2019). EGFR-Dependent IL8 Production by Airway Epithelial Cells After Exposure to the Food Flavoring Chemical 2,3-Butanedione. Toxicol. Sci. 169, 534-542.

Khan, E.M., Lanir, R., Danielson, A.R., and Goldkorn, T. (2008). Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking. FASEB J. 22, 910-917.

Kiley, S.C., and Chevalier, R.L. (2007). Species differences in renal Src activity direct EGF receptor regulation in life or death response to EGF. Am. J. Physiol. Renal Physiol. 293, F895-F903.

Kim, H.J., Park, Y.-D., Moon, U.Y., Kim, J.-H., Jeon, J.H., Lee, J.-G., et al. (2008). The role of Nox4 in oxidative stress–induced MUC5AC overexpression in human airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 39, 598-609.

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