Aop: 148

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [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

Authors

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 (Karsta.Luettich@pmi.com); 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
Karsta Luettich   (email point of contact)

Contributors

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
  • Marja Talikka

Status

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 September 13, 2021 05:07
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, Metaplasia of goblet cells August 23, 2021 03:12
Occurrence, Hyperplasia of goblet cells September 21, 2021 04:46
Increase, Proliferation of goblet cells August 20, 2021 01:52
Decrease, Apoptosis of ciliated epithelial cells August 17, 2021 01:45
Activation, EGFR August 16, 2021 08:33
Increase, Mucin production August 23, 2021 03:14
Decrease, Lung function September 08, 2021 04:54
Chronic, Mucus hypersecretion August 25, 2021 01:25
Activation, EGFR leads to Decreased ciliated cell apoptosis August 27, 2021 10:12
Decreased ciliated cell apoptosis leads to Goblet cell metaplasia August 25, 2021 11:07
Activation, EGFR leads to Goblet cell metaplasia August 27, 2021 04:26
Goblet cell metaplasia leads to Chronic, Mucus hypersecretion August 27, 2021 05:36
Activation, EGFR leads to Increased goblet cell proliferation August 27, 2021 10:05
Increased goblet cell proliferation leads to Goblet cell hyperplasia August 27, 2021 07:13
Goblet cell hyperplasia leads to Chronic, Mucus hypersecretion August 30, 2021 03:56
Activation, EGFR leads to Increase, Mucin production August 27, 2021 07:09
Increase, Mucin production leads to Chronic, Mucus hypersecretion August 30, 2021 08:19
Chronic, Mucus hypersecretion leads to Decreased lung function August 30, 2021 10:32
Reactive oxygen species August 15, 2017 10:43

Abstract

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

Mucus hypersecretion in the airways is a key characteristic of many lung diseases, including asthma, cystic fibrosis and chronic bronchitis, all of which are characterized by decreased lung function (Yoshida and Tuder, 2007). In patients with chronic bronchitis, mucus hypersecretion 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 and Criner, 2015; Yoshida and 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). This AOP for decreased lung function originates in oxidative stress-mediated epidermal growth factor receptor (EGFR) activation in the airway epithelium. It describes the subsequent key events on the cellular and organ level that need to take place to culminate in the adevrse outcome. Understanding how the chronic exposure to inhaled toxicants leads to mucus hypersecretion will be relevant to risk assessment of airborne pollutant and cigarette smoke exposure and how they contribute to the development and progression of the disease. Additionally, understanding the molecular underpinnings of these processes can aid in informing regulatory decision-making to assess the impact of inhalation toxicants on public health outcomes. 

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 and Criner, 2015; Yoshida and 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 as well as 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 and 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

Events:

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 914 Decrease, Apoptosis of ciliated epithelial cells Decreased ciliated cell apoptosis
3 KE 920 Occurrence, Metaplasia of goblet cells Goblet cell metaplasia
4 KE 923 Increase, Proliferation of goblet cells Increased goblet cell proliferation
5 KE 921 Occurrence, Hyperplasia of goblet cells Goblet cell hyperplasia
6 KE 1251 Chronic, Mucus hypersecretion Chronic, Mucus hypersecretion
7 KE 962 Increase, Mucin production Increase, Mucin production
8 AO 1250 Decrease, Lung function Decreased lung function

Relationships Between Two Key Events (Including MIEs and AOs)

This 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

Stressors

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
Mixed 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 and ultimately lead to lung function decline may 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 Voynow, 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 and Fong, 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.

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

Biological Plausibility

EGFR activation in human, mouse and rat is well documented and EGFR ligands and EGFR are orthologous in these species. EGFR activation by ligand binding and ligand-independent mechanisms are supported by studies with EGFR inhibitors such as AG1478 and BIBX 1522, efficiently abrogating downstream signaling and, hence, cell proliferation and survival (Tyner et al., 2006; Casalino-Matsuda et al., 2006; Song et al., 2016). However, evidence for a specific EGFR-mediated effect in airway goblet or ciliated cells is limited and partially correlative, so biological plausibility for EGFR activation increasing proliferation of goblet cells and decreasing apoptosis of ciliated cells is only moderate. 

Another gap in current knowledge pertains to how inhibition of ciliated cell apoptosis leads to transdifferentiation that eventually contributes to an increase in goblet cell numbers. The available evidence is indirect or correlative (Tyner et al., 2006; Silva et al., 2012; Reader et al., 2003; Turner et al., 2011; Ayers et al., 1988; Jefferey et al., 1984). It also is not in agreement with other studies showing that ciliated cells do not give rise to goblet cells during airway remodeling in rodents and humans and those that provide evidence for increased goblet cell proliferation (Lumsden et al., 1984; Casalino-Matsuda et al., 2006; Taniguchi et al., 2011; Hays et al., 2006; Tesfaigzi et al., 2004). Therefore, we consider biological plausibility for this KER to be moderate.

Transcriptional regulation of MUC5AC expression in the airways has been directly linked to EGFR-mediated activation of Sp-1 (Oyanagi et al., 2016, Hewson et al., 2004; Barbier et al., 2012). However, since the MUC5AC promoter has multiple transcription factor binding sites, it is not unlikely that alternative pathways 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). Since it is not clear whether such alternative routes to mucin overproduction also require EGFR signaling, the combined evidence supports moderate biological plausibility.

Studies in airway epithelial cells and in rats demonstrated that GCH/M and increased mucin production following infection with M. pneumonia and exposure to PM2.5, acrolein or cigarette smoke can be greatly diminished by (pre-)treatment with EGFR inhibitors (Val et al., 2012; Takeyama et al., 2001; Lee et al., 2000; Hegab et al., 2007; Deshmukh et al., 2005; Deshmukh et al., 2008), supporting biological plausibility for this KER. However, owing to the fact that there is only correlational evidence linking increased goblet cell numbers to increased mucin production that coincides with strong EGFR expression in human airways (Kim et al., 2004; Burgel et al., 2000), plausibility is moderate.

Clinical studies showed that MUC5AC expression in bronchial epithelium was inversely correlated with FEV1 (% predicted) and with FEV1/FVC ratio (Caramori et al., 2009; Innes et al., 2006), and epidemiological evidence indicates a link between mucus hypersecretion and decreased lung function (Allinson et al., 2015; Pistelli et al., 2003; Vestbo et al., 1996). As a cause-effect relationship cannot be conclusively proven, these findings support moderate biological plausibility.

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

There is good quantitative understanding of how EGFR signaling 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 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, 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 KERs on the tissue and organism levels 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 functionfor most environmental pollutants, 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.

References

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

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