Aop: 148


A descriptive title which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

EGFR Activation Leading to Decreased Lung Function

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Decreased lung function

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help


List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Philip Morris International: Karsta Luettich (; Marja Talikka; Julia Hoeng

British American Tobacco: Frazer Lowe; Linsey Haswell; Marianna Gaca

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Cataia Ives   (email point of contact)


List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Karsta Luettich
  • Cataia Ives


The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.51 Included in OECD Work Plan
This AOP was last modified on April 05, 2021 18:16
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Occurrence, Transdifferentiation of ciliated epithelial cells April 06, 2018 02:29
Occurrence, Metaplasia of goblet cells April 09, 2018 04:07
Occurrence, Hyperplasia of goblet cells April 06, 2018 02:52
Increase, Proliferation of goblet cells April 06, 2018 03:31
Activation, Sp1 May 22, 2018 20:53
Decrease, Apoptosis of ciliated epithelial cells April 06, 2018 05:01
Activation, EGFR March 22, 2018 05:49
Increase, Mucin production April 06, 2018 08:33
Decrease, Lung function April 09, 2018 03:56
Chronic, Mucus hypersecretion April 06, 2018 09:47
Occurrence, Transdifferentiation of ciliated epithelial cells leads to Occurrence, Metaplasia of goblet cells April 26, 2018 00:17
Increase, Proliferation of goblet cells leads to Goblet cell hyperplasia April 26, 2018 00:15
Activation, EGFR leads to Increase, Mucin production April 27, 2018 08:58
Activation, Sp1 leads to Increase, Mucin production April 20, 2018 03:33
Decrease, Apoptosis of ciliated epithelial cells leads to Occurrence, Transdifferentiation of ciliated epithelial cells April 25, 2018 01:00
Activation, EGFR leads to Decrease, Apoptosis of ciliated epithelial cells April 25, 2018 06:34
Activation, EGFR leads to Activation, Sp1 April 25, 2018 00:49
Activation, EGFR leads to Occurrence, Transdifferentiation of ciliated epithelial cells April 26, 2018 04:38
Activation, EGFR leads to Increase, Proliferation of goblet cells April 27, 2018 02:13
Goblet cell hyperplasia leads to Increase, Mucin production May 22, 2018 21:36
Occurrence, Metaplasia of goblet cells leads to Increase, Mucin production May 22, 2018 21:45
Chronic, Mucus hypersecretion leads to Decrease, Lung function May 17, 2018 02:45
Increase, Mucin production leads to Chronic, Mucus hypersecretion May 17, 2018 02:16
Reactive oxygen species August 15, 2017 10:43


In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

Background (optional)

This optional subsection should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

The lungs’ mucous barrier is a natural defense against the harmful effects of inhaled xenobiotics, including respiratory toxicants and pathogens (Rubin, 2014). Under physiological conditions, foreign particles are trapped in mucus and eliminated from the airways via mucociliary clearance (Rose and Voynow, 2006). However, excessive mucus production can lead to impaired mucociliary clearance and airway obstruction and, eventually, result in decreased lung function (Nadel, 2013). Excessive mucus production, or mucus hypersecretion, is a characteristic feature of chronic diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, all of which pose a significant public health burden. Of note, exposure to cigarette smoke, occupational respiratory hazards, and air pollutants are clearly linked to the development of COPD, which is predicted to become the third leading cause of death worldwide by 2030 (Viegi et al., 2007; WHO, 2008). While regulation and public health measures seek to minimize exposures and thereby the incidence of the disease, airflow obstruction can be seen in approximately 25% of adults aged 40 and over globally (Diaz-Guzman and Mannino, 2014). Mucus hypersecretion in chronic bronchitis is characterized by an increase in the number of goblet cells, mucin synthesis and mucus secretion which can result in airway obstruction, decreased peak expiratory flow and respiratory muscle weakness (Kim & Criner, 2015; Yoshida & Tuder, 2007). Epidermal growth factor receptor (EGFR)-mediated signaling has been identified as the key pathway that leads to airway mucus hypersecretion (Burgel and Nadel, 2004), and redox signaling as the major initiator of receptor activation (Heppner and van der Vliet, 2016). Therefore, we believe that the molecular initiating event (MIE) of this AOP is oxidative stress leading to activation (phosphorylation) of EGFR on the surface of lung epithelial cells. Exogenous oxidative stress, e.g. arising from exposure to airborne toxicants and pathogens, as well as oxidative stress induced by inflammatory responses, mediates 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. Of note, ligand binding in itself has been identified as a source of reactive oxygen species (ROS), and specifically of hydrogen peroxide (H2O2), which function as second messengers potentially perpetuating the ensuing EGFR activation through chemical modification of the receptor (Paulsen et al., 2011; DeYulia et al., 2005). In addition, the presence of ROS may also contribute to EGFR activation by chemically modifying the receptor, thereby altering its structure and enhancing its kinase activity (Paulsen et al., 2011; Wu et al. 1999). 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). Subsequent stimulation by proinflammatory stimuli such as the Th2 cytokines interleukin (IL)-4 and IL-13 then promotes transdifferentiation of ciliated cells into goblet cells, thereby increasing the number of goblet cells (“second hit hypothesis”; Curran and Cohn, 2010). Alternatively, downstream activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, also known as Raf/Ras/MAPK/ERK pathway, increases airway epithelial cell proliferation or Sp-1 transcription factor-mediated mucin gene and protein expression. Together these processes ultimately lead to goblet cell hyperplasia/metaplasia (GCH/GCM) and mucus hypersecretion (Rogers, 2007). If oxidative stress persists, e.g. under conditions of chronic exposure to respiratory toxicants, airway remodeling will cease being a physiological stress response aimed at eliminating the potential hazard and regaining the balance of a healthy airway epithelium. Instead, airway remodeling will result in airway narrowing, and in combination with GCH and chronic mucus production, lung function will begin to decline (Aoshiba and Nagai, 2004). Furthermore, over time, chronic mucus hypersecretion may contribute to a progressive deterioration in lung function (Kim & Criner, 2015).

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 941 Activation, EGFR Activation, EGFR
2 KE 919 Occurrence, Transdifferentiation of ciliated epithelial cells Occurrence, Transdifferentiation of ciliated epithelial cells
3 KE 920 Occurrence, Metaplasia of goblet cells Occurrence, Metaplasia of goblet cells
4 KE 921 Occurrence, Hyperplasia of goblet cells Goblet cell hyperplasia
5 KE 923 Increase, Proliferation of goblet cells Increase, Proliferation of goblet cells
6 KE 924 Activation, Sp1 Activation, Sp1
7 KE 914 Decrease, Apoptosis of ciliated epithelial cells Decrease, Apoptosis of ciliated epithelial cells
8 KE 962 Increase, Mucin production Increase, Mucin production
9 KE 1251 Chronic, Mucus hypersecretion Chronic, Mucus hypersecretion
10 AO 1250 Decrease, Lung function Decrease, Lung function

Relationships Between Two Key Events (Including MIEs and AOs)

TESTINGThis table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and WoE summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help


The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, 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). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help
Name Evidence Term
Reactive oxygen species High

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
Adult High
Juvenile Low

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. 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 Moderate NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

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

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Life Stage Applicability

EGFR activation leading to mucus hypersecretion is predominantly studied in adults; however, it has been shown to also occur in pediatric asthma and bronchitis (Rogers, 2003; Parker et al., 2015). Nevertheless, the environmental exposures that induce EGFR activation apply more to adults who are more likely to be exposed to these stimulants over time (cigarette smoke, particulate matter).

Taxonomic Applicability

The evidence presented here is derived from both human and rodent biological systems. In vitro and in vivo studies in these systems have been performed to clarify the mechanisms of EGFR activation and mucus hypersecretion by studying the increase in goblet cells and subsequent increase in mucin transcript and protein expression as well as mucus production (Rose and Vounow, 2006; Rogers, 2007). In summary, these evidences suggest that the majority of KEs are preserved across small rodents and humans. There are also several clinical studies on mucus hypersecretion and how it affects lung function in humans with chronic bronchitis, asthma and other chronic lung diseases. However, the link between mucus hypersecretion and airflow obstruction is much less supported by studies in laboratory animals where the human disease phenotype cannot be modelled in its entirety and traditional lung function measurements are difficult (Vlahos et al., 2014; Nikula et al., 2000).

Sex Applicability

At times, clinical evidence linked to occupational exposures is derived from a majority of male subjects, which could be related to a male predominance in certain professions (Eng et al., 2011; Kennedy et al., 2007). Similarly, in most Western countries, cigarette smoking is still more prevalent in men than in women, although this gap has been closing steadily over the past decades (Syamlal et al., 2014; Hitchman et al., 2011). Nevertheless, the available in vivo and clinical evidence suggest that there is no remarkable gender difference.

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

Molecular Initiating Event Summary, Key Event Summary

EGFR signaling is considered critical for mucus hypersecretion and goblet cell hyperplasia (GCH)/goblet cell metaplasia (GCM)(Curran & Cohn, 2010), and numerous studies indicate that inhibition of EGFR decreases mucin production or goblet cell numbers (Tyner et al., 2006; Shim et al., 2001; Takeyama et al., 2008; Lee et al., 2011; Taniguchi et al., 2011; Song et al., 2016; Takeyama et al., 2011). EGFR blockade also was reported to prevent an increase in goblet cell numbers and cause activation of caspase-3 and loss of ciliated cells, indicating that EGFR is essential for decreased ciliated cell apoptosis (Tyner et al., 2006). However, there is also evidence supporting decreased apoptosis in airway goblet cells in vitro, in a mouse model of asthma, and in rats following intratracheal lipopolysaccharide (LPS) instillation as a result of EGFR activation (Casalino-Matsuda et al., 2006; Song et al., 2016; Tesfaigzi, 2006). Whether the latter only occurs once GCH/GCM is established, as indicated by Harris et al. (2005), or whether additional events are required to maintain GCH/GCM, is currently unclear.

Sp-1 binding sites are required for active MUC5AC gene expression (Hewson et al., 2004), and Sp-1-mediated mucin expression can be blocked by the Sp-1 inhibitor mithramycin A (Lee et al., 2011; Wu et al., 2007). However, since the MUC5AC promoter has multiple transcription factor binding sites, it is likely that alternative pathways might also contribute to increased mucin production, such as activation of HIF-1α or decreased FOXA2 expression (Hao et al., 2014; Kim et al., 2014; Wan et al., 2004).

Mucus hypersecretion is a physiological response to inhalation exposures such as pollutants or infectious agents. As such, it is typically of short duration and does not pose a major problem to normal lung function. However, in the presence of GCH, increased mucus production may decrease airflow. Since this may be accompanied by impaired mucociliary clearance and ineffective cough (Ramos et al., 2014), and owing to the lack of direct evidence, it is currently unclear whether chronic mucus hypersecretion alone is sufficient to affect a decrease in lung function.

Although some KERs may be executed in parallel to and independent of each other, all KEs together contribute to mucus hypersecretion as a result of EGFR activation by oxidative stress.

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

Summary Table

Empirical Support for KERs

Defining question: Does empirical evidence support that a change in KEup leads to an appropriate change in KEdown? Does KEup occur at lower doses, earlier time points, and higher in incidence than KEdown? Inconsistencies?

High (Strong)

Multiple studies showing dependent change in both events following exposure to a wide range of specific stressors. No or few critical data gaps or conflicting data.


Demonstrated dependent change in both events following exposure to a small number of stressors. Some inconsistencies with expected pattern that can be explained by various factors.

Low (Weak)

Limited or no studies reporting dependent change in both events following exposure to a specific stressor, and/or significant inconsistencies in empirical support across taxa and species.

Oxidative stress directly leading to EGFR activation


Various sources of ROS, including glucose oxidase, xanthine/xanthine oxidase, acrolein, H2O2, cigarette smoke extract, PMA, TCDD, and supernatant from activated neutrophils or eosinophils cause a measurable, rapid increase in EGFR phosphorylation in human airway epithelial cells and the lungs of F344 rats (Burgel et al., 2001; Casalino-Matsuda et al., 2004; Casalino-Matsuda et al., 2006; Deshmukh et al., 2008; Hewson et al., 2004; Kim et al., 2008; Lee et al., 2011; Qi et al., 2010; Ravid et al., 2002; Takeyama et al., 2000; Takeyama et al., 2001b; Yu et al., 2011; Yu et al., 2015). In some instances, the response was dose-dependent (Hewson et al., 2004; Ravid et al., 2002); in others, it was directly linked to GCH or increased mucin production (Casalino-Matsuda et al., 2006; Takeyama et al., 2001b). Moreover, antioxidant treatment prevented EGFR activation and diminished downstream mucin overexpression (Casalino-Matsuda et al., 2006).

EGFR activation indirectly leading to decreased epithelial cell apoptosis


Oxidative stress increased Bcl-2 mRNA and protein levels in human and rat airway goblet cells (Casalino-Matsuda et al., 2006; Foster et al., 2003; Lee et al., 2011; Tesfaigzi et al., 1998; Tesfaigzi et al., 2000). Neutralization of Bcl-2 expression in rat nasal epithelium reduced GCM (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).

Decreased epithelial cell apoptosis directly leading to transdifferentiation into goblet cells


There is no direct evidence linking decreased apoptosis in ciliated cells to their transdifferentiation. Co-localization of EGFR and β-tubulin but not CCSP or MUC5AC expression was observed in Sendai virus-infected mouse airways and in the airways of asthma patients (Takeyama et al., 2001a; Tyner et al., 2006). In addition, ciliated cell tagging studies in vitro indicated that the number of ciliated cells decreases following treatment with IL-13, while the number of goblet cells increases (Turner et al., 2011). Together these studies are supportive of ciliated cells transdifferentiating into goblet cells. 

EGFR activation directly leading to increased epithelial cell proliferation


Treatment of human airway epithelial cells with oxidative stressors, EGFR ligands, or IL-13 was shown to increase the number of MUC5AC-positive (i.e. goblet) cells (Casalino-Matsuda et al., 2006; Hirota et al., 2012). Increased proliferation was observed in rat conjunctival goblet cells following treatment with EGFR ligands (Gu et al., 2008; Shatos et al., 2008). In addition, 50% of goblet cells were BrdU-positive in rat airways following LPS instillation, suggesting that they may have been derived from proliferating cells (Tesfaigzi et al., 2004).

EGFR activation directly leading to Sp-1 activation


Treatment of H292 cells with PMA dose-dependently increased MUC5AC mRNA and protein production, shown to be dependent on ligand-dependent EGFR phosphorylation and subsequent Sp-1-mediated transactivation of the MUC5AC promoter (Hewson et al., 2004). Moreover, Sp-1 phosphorylation and MUC5AC promoter activity increased in TCDD-treated NHBECs, and increased promoter activity was suppressed in the presence of the EGFR inhibitor AG1478 (Lee et al., 2011).

EGFR activation indirectly leads to increased mucin production


Oxidative stress increased EGFR phosphorylation and MUC5AC gene and protein expression in human lung and nasal epithelial cells, as well as in the airways of mice and rats (Casalino-Matsuda et al., 2006; Deshmukh et al., 2008; Hao et al., 2014; Hegab et al., 2007; Kim et al., 2010; Val et al., 2012). Pre-treatment with catalase, glutathione, AG1478, erlotinib, gefitinib, or a neutralizing antibody preventing EGFR ligand binding markedly reduced mucin production.

Increased epithelial cell proliferation directly leading to GCH


Inferred: The term ‘hyperplasia’ refers to an increase in a tissue or organ that is linked to an increase in cell number or cell size. Therefore, increased proliferation can be considered a root cause of GCH.

Transdifferentiation into goblet cells directly leading to GCM


Inferred: Following injury, airway epithelial repair is accomplished by (transient) remodeling processes. In the absence of cell proliferation, this remodeling is thought to be facilitated by transdifferentiation, i.e. the generation of specialized cell types, such as goblet cells, from other specialized cells, such as ciliated and club cells (Evans et al., 2004; Tesfaigzi, 2006).

Sp-1 activation directly leading to increased mucin production


Treatment of A549 cells with cigarette smoke extract increased MUC5AC promoter activity, which was accompanied by an increase in Sp-1 protein expression, nuclear translocation, and Sp-1-DNA-binding (Di et al., 2012). Similarly, increased MUC5AC gene and protein expression in H292 cells infected with IVA was shown to be linked to activation of Sp-1 (Barbier et al., 2012).

Increased mucin production directly leading to mucus hypersecretion


Inferred: Increased mucin production is a requirement in states of mucus hypersecretion to restore depleted mucin stores (Rose and Voynow, 2006). Mucus hypersecretion is a cardinal feature of chronic lung diseases and has been linked to both increased intraluminal mucus volume (Aikawa et al., 1989), a measure of mucus hypersecretion, and increased mucin production.

GCH/GCM directly leading to mucus hypersecretion


Inferred:  According to Rose et al., “Secretory cell hyperplasia is a prerequisite for sustained mucus hypersecretion/mucin overproduction” (Rose and Voynow, 2006).

Chronic mucus hypersecretion directly leads to decreased lung function


GCH and MUC5AC expression was increased in the airways of COPD patients compared with non-COPD patients (with normal lung function) (Ma et al., 2005). The volume of epithelial mucin stores was larger in bronchial biopsies from smokers compared with those without airflow obstruction, and correlated with the FEV1/FVC ratio (Innes et al., 2006).  MUC5AC expression in bronchial epithelium was inversely correlated with FEV1 (% predicted) (Caramori et al., 2009). Epidemiological data indicate that self-reported symptoms, including chronic sputum production and/or chronic cough, in middle-aged current smokers increased the likelihood of airflow limitation at later stages of life, and that lung function declines more rapidly the longer chronic mucus hypersecretion persists, at least in this middle-aged group (Allinson et al., 2015; Pistelli et al., 2003; Vestbo et al., 1996).

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Summary Table

There is good quantitative understanding of how oxidative stress affects EGFR signaling and influences mucus production, epithelial cell proliferation, apoptosis, and transdifferentiation, individually assayed. In addition, in the majority of these studies, the summary evidence indicates dose-response relationships, time-response relationships, and causality for oxidative stress-induced EGFR activation leading to increased cell proliferation, lending strong support for these KERs. However, quantitative knowledge is lacking with respect to the identity of airway epithelial cells undergoing proliferation and apoptosis, which makes empirical support for these KERs weak. Furthermore, while cause-effect relationships can be derived from studies investigating Sp-1 activation, dose-response relationships are difficult to derive. Moreover, data for increased mucin production and mucus hypersecretion at the organism level are mainly derived from surrogate measures, and while those may not adequately reflect quantitative mucus production, they are accepted in the clinical community as an indicator of chronic bronchitis. Taken together, the quantitative evidence for the KEs and KERs on the tissue and organism level are moderate at best.

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

The future application of this AOP lies in its potential for predicting decreased lung function in humans exposed to potentially harmful inhaled substances. This becomes especially pertinent as impaired lung function carries a significant risk of morbidity and mortality. Owing to the long latency period between exposure and detectable decreases in lung function, together with the fact that lung function tests alone may not be sufficiently sensitive to account for early lung damage that remains asymptomatic (Celli et al., 2003), means for early identification of potentially hazardous exposures are critical for the development of appropriate public health interventions.


List the bibliographic references to original papers, books or other documents used to support the AOP. More help

Aoshiba, K., & Nagai, A. (2004). Differences in airway remodeling between asthma and chronic obstructive pulmonary disease. Clin. Rev. Allergy & Immunol. 27, 35-43.

Barbier, D., Garcia-Verdugo, I., Pothlichet, J., Khazen, R., Descamps, D., Rousseau, K., Thornton, D., Si-Tahar, M., Touqui, L., Chignard, M., et al. (2012). Influenza A Induces the Major Secreted Airway Mucin MUC5AC in a Protease–EGFR–Extracellular Regulated Kinase–Sp1–Dependent Pathway. Am. J. Respir. Cell Mol. Biol. 47, 149–157.

Booth, B.W., Adler, K.B., Bonner, J.C., Tournier, F., and Martin, L.D. (2001). Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-alpha. Am. J. Respir. Cell Mol. Biol. 25, 739–743.

Booth, B.W., Sandifer, T., Martin, E.L., and Martin, L.D. (2007). IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17. Respir. Res. 8, 51.

Burgel, P.-R., Escudier, E., Coste, A., Dao-Pick, T., Ueki, I. F., Takeyama, K., Shim, J. J., Murr, A. H., Nadel, J. A. (2000). Relation of epidermal growth factor receptor expression to goblet cell hyperplasia in nasal polyps. J. Allergy Clin. Immunol. 106, 705-712.

Burgel, P.-R., Lazarus, S. C., Tam, D. C.-W., Ueki, I. F., Atabai, K., Birch, M., & Nadel, J. A. (2001). Human eosinophils induce mucin production in airway epithelial cells via epidermal growth factor receptor activation. J. Immunol. 167(10), 5948-5954.

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

Burgel, P., & 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., Monzon, M., Day, A., and Forteza, R. (2009). Hyaluronan fragments/CD44 mediate oxidative stress-induced MUC5B up-regulation in airway epithelium. Am. J. Respir. Cell. Mol. Biol. 40, 277–285.

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.

Celli, B., Halbert, R., Isonaka, S., & Schau, B. (2003). Population impact of different definitions of airway obstruction. Eur. Respir. J. 22(2), 268-273.

Coles, S.J., Levine, L.R., and Reid, L. (1979). Hypersecretion of mucus glycoproteins in rat airways induced by tobacco smoke. Am. J. Pathol. 94, 459–471.

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.

DeYulia, G. J., Cárcamo, J. M., Bórquez-Ojeda, O., Shelton, C. C., & Golde, D. W. (2005). Hydrogen peroxide generated extracellularly by receptor–ligand interaction facilitates cell signaling. PNAS 102, 5044-5049.

DeYulia Jr., G. J., & 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.

Diaz-Guzman, E., & Mannino, D. M. (2014). Epidemiology and prevalence of chronic obstructive pulmonary disease. Clin. Chest Med. 35, 7-16.

Dohrman, A., Miyata, S., Gallup, M., Li, J.D., Chapelin, C., Coste, A., Escudier, E., Nadel, J., and Basbaum, C. (1998). Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria. Biochim. Biophys. Acta 1406, 251–259.

Gao, W., Li, L., Wang, Y., Zhang, S., Adcock, I. M., Barnes, P. J., Huang, M., Yao, X. (2015). Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease? Respirology 20, 722-729.

Gomperts, B.N., Kim, L.J., Flaherty, S.A., and Hackett, B.P. (2007). IL-13 regulates cilia loss and foxj1 expression in human airway epithelium. Am. J. Respir. Cell Mol. Biol. 37, 339–346.

Gu, J., Chen, L., Shatos, M.A., Rios, J.D., Gulati, A., Hodges, R.R., and Dartt, D.A. (2008). Presence of EGF growth factor ligands and their effects on cultured rat conjunctival goblet cell proliferation. Exp. Eye Res. 86, 322–334.

Hao, Y., Kuang, Z., Jing, J., Miao, J., Mei, L.Y., Lee, R.J., Kim, S., Choe, S., Krause, D.C., and Lau, G.W. (2014). Mycoplasma pneumoniae Modulates STAT3-STAT6/EGFR-FOXA2 Signaling To Induce Overexpression of Airway Mucins. Infect. Immun. 82, 5246–5255.

Harkema, J., and Hotchkiss, J. (1993). Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: novel animal models to study toxicant-induced epithelial transformation in airways. Toxicol Lett 68, 251–263.

Harkema, J., and Wagner, J. (2002). Non-allergic models of mucous cell metaplasia and mucus hypersecretion in rat nasal and pulmonary airways. Novartis Found Symp 248, 181–197; discussion 197–200, 277–282.

Harris, J. F., Fischer, M. J., Hotchkiss, J. R., Monia, B. P., Randell, S. H., Harkema, J. R., & Tesfaigzi, Y. (2005). Bcl-2 sustains increased mucous and epithelial cell numbers in metaplastic airway epithelium. Am. J. Respir. Crit. Care Med. 171, 764-772.

Hewson, C., Edbrooke, M., and Johnston, S. (2004). PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol 344, 683–695.

Ikari, A., Atomi, K., Takiguchi, A., Yamazaki, Y., Miwa, M., and Sugatani, J. (2009). Epidermal growth factor increases claudin-4 expression mediated by Sp1 elevation in MDCK cells. Biochem. Biophys. Res. Commun. 384, 306–310.

Kim, V., and Criner, G. (2015). The chronic bronchitis phenotype in chronic obstructive pulmonary disease: features and implications. Curr Opin Pulm Med 21, 133–141.

Kim, H. J., Park, Y.-D., Moon, U. Y., Kim, J.-H., Jeon, J. H., Lee, J.-G., Bae, Y. S., Yoon, J.-H. (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.

Kim, H. J., Ryu, J.-H., Kim, C.-H., Lim, J. W., Moon, U. Y., Lee, G. H., Lee, J. G., Baek, S. J., Yoon, J.-H. (2010). Epicatechin gallate suppresses oxidative stress–induced MUC5AC overexpression by interaction with epidermal growth factor receptor. Am. J. Respir. Cell Mol. Biol. 43, 349-357.

Kim, J.-H., Jung, K.-H., Han, J.-H., Shim, J.-J., In, K.-H., Kang, K.-H., & Yoo, S.-H. (2004). Relation of epidermal growth factor receptor expression to mucus hypersecretion in diffuse panbronchiolitis. Chest 126, 888-895.

Kim, J. H., Lee, S. Y., Bak, S. M., Suh, I. B., Lee, S. Y., Shin, C., Shim, J. J., In, K. H., Kang, K. H., Yoo, S. H. (2004). Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia. Am. J. Physiol Lung Cell. Mol. Physiol. 287, L127-L133.

Lamb, D., and Reid, L. (1968). Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchial epithelium during exposure to sulphur dioxide. J. Pathol. Bacteriol. 96, 97–111.

Laoukili, J., Perret, E., Willems, T., Minty, A., Parthoens, E., Houcine, O., Coste, A., Jorissen, M., Marano, F., Caput, D., et al. (2001). IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J. Clin. Invest. 108, 1817–1824.

Lee, H.-M., Takeyama, K., Dabbagh, K., Lausier, J.A., Ueki, I.F., and Nadel, J.A. (2000). Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L185–L192.

Lee, Y.C., Oslund, K.L., Thai, P., Velichko, S., Fujisawa, T., Duong, T., Denison, M.S., and Wu, R. (2011). 2,3,7,8-Tetrachlorodibenzo-p-dioxin–Induced MUC5AC Expression. Am. J. Respir. Cell Mol. Biol. 45, 270–276.

Lu, X.-F., Li, E.-M., Du, Z.-P., Xie, J.-J., Guo, Z.-Y., Gao, S.-Y., Liao, L.-D., Shen, Z.-Y., Xie, D., and Xu, L.-Y. (2010). Specificity protein 1 regulates fascin expression in esophageal squamous cell carcinoma as the result of the epidermal growth factor/extracellular signal-regulated kinase signaling pathway activation. Cell. Mol. Life Sci. CMLS 67, 3313–3329.

Merchant, J.L., Shiotani, A., Mortensen, E.R., Shumaker, D.K., and Abraczinskas, D.R. (1995). Epidermal growth factor stimulation of the human gastrin promoter requires Sp1. J. Biol. Chem. 270, 6314–6319.

Nadel, J. A. (2013). Mucous hypersecretion and relationship to cough. Pulm. Pharmacol. Thera. 26, 510-513.

Nagai, A., Thurlbeck, W.M., and Konno, K. (1995). Responsiveness and variability of airflow obstruction in chronic obstructive pulmonary disease. Clinicopathologic correlative studies. Am. J. Respir. Crit. Care Med. 151, 635–639.

Park, K.-S., Wells, J.M., Zorn, A.M., Wert, S.E., Laubach, V.E., Fernandez, L.G., and Whitsett, J.A. (2006). Transdifferentiation of ciliated cells during repair of the respiratory epithelium. Am. J. Respir. Cell Mol. Biol. 34, 151–157.

Parker, J.C., Douglas, I., Bell, J., Comer, D., Bailie, K., Skibinski, G., Heaney, L.G., and Shields, M.D. (2015). Epidermal Growth Factor Removal or Tyrphostin AG1478 Treatment Reduces Goblet Cells & Mucus Secretion of Epithelial Cells from Asthmatic Children Using the Air-Liquid Interface Model. PloS One 10, e0129546.

Perrais, M., Pigny, P., Copin, M., Aubert, J., and Van Seuningen, I. (2002). Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1. J Biol Chem 277, 32258–32267.

Rawlins, E.L., and Hogan, B.L.M. (2008). Ciliated epithelial cell lifespan in the mouse trachea and lung. Am. J. Physiol. - Lung Cell. Mol. Physiol. 295, L231–L234.

Rawlins, E.L., Ostrowski, L.E., Randell, S.H., and Hogan, B.L.M. (2007). Lung development and repair: contribution of the ciliated lineage. Proc. Natl. Acad. Sci. U. S. A. 104, 410–417.

Rogers, D.F. (2003). Pulmonary mucus: Pediatric perspective. Pediatr. Pulmonol. 36, 178–188.

Rogers, D. F. (2007). Physiology of airway mucus secretion and pathophysiology of hypersecretion. Respir. Care 52, 1134-1149.

Saetta, M., Turato, G., Baraldo, S., Zanin, A., Braccioni, F., Mapp, C., Maestrelli, P., Cavallesco, G., Papi, A., and Fabbri, L. (2000). Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 161, 1016–1021.

Shao, M., Nakanaga, T., and Nadel, J. (2004). Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. Am J Physiol Lung Cell Mol Physiol 287, L420–L427.

Shatos, M.A., Ríos, J.D., Horikawa, Y., Hodges, R.R., Chang, E.L., Bernardino, C.R., Rubin, P.A.D., and Dartt, D.A. (2003). Isolation and characterization of cultured human conjunctival goblet cells. Invest. Ophthalmol. Vis. Sci. 44, 2477–2486.

Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., Tam, D.C., and Nadel, J.A. (2001). IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L134–L140.

Shimizu, T., Takahashi, Y., Kawaguchi, S., and Sakakura, Y. (1996). Hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium induced by endotoxin. Am. J. Respir. Crit. Care Med. 153, 1412–1418.

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.

Takeyama, K., Dabbagh, K., Lee, H., Agustí, C., Lausier, J., Ueki, I., Grattan, K., and Nadel, J. (1999). Epidermal growth factor system regulates mucin production in airways. Proc Natl Acad Sci U A 96, 3081–3086.

Takeyama, K., Jung, B., Shim, J., Burgerl, P., Dao-Pick, T., Ueki, I., Protin, U., Kroschel, P., and Nadel, J. (2001). Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am J Physiol Lung Cell Mol Physiol 280, L165–L172.

Takeyama, K., Tamaoki, J., Kondo, M., Isono, K., and Nagai, A. (2008). Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen. Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol. 38, 857–865.

Tamaoki, J., Isono, K., Takeyama, K., Tagaya, E., Nakata, J., and Nagai, A. (2004). Ultrafine carbon black particles stimulate proliferation of human airway epithelium via EGF receptor-mediated signaling pathway. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L1127–L1133.

Taniguchi, K., Yamamoto, S., Aoki, S., Toda, S., Izuhara, K., and Hamasaki, Y. (2011). Epigen is induced during the interleukin-13-stimulated cell proliferation in murine primary airway epithelial cells. Exp. Lung Res. 37, 461–470.

Turner, J., Roger, J., Fitau, J., Combe, D., Giddings, J., Heeke, G.V., and Jones, C.E. (2011). Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway epithelium. Am. J. Respir. Cell Mol. Biol. 44, 276–284.

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.

Wu, D.Y., Wu, R., Reddy, S.P., Lee, Y.C., and Chang, M.M.-J. (2007). Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate. Am. J. Pathol. 170, 20–32.

Xu, J., Zhao, M., and Liao, S. (2000). Establishment and pathological study of models of chronic obstructive pulmonary disease by SO2 inhalation method. Chin Med J Engl 113, 213–216.

Yu, H., Li, Q., Zhou, X., Kolosov, V., and Perelman, J. (2011). Role of hyaluronan and CD44 in reactive oxygen species-induced mucus hypersecretion. Mol Cell Biochem 352, 65–75.

Zheng, X.-L., Matsubara, S., Diao, C., Hollenberg, M.D., and Wong, N.C.W. (2001). Epidermal Growth Factor Induction of Apolipoprotein A-I Is Mediated by the Ras-MAP Kinase Cascade and Sp1. J. Biol. Chem. 276, 13822–13829.