Aop: 148

Title

A descriptive phrase 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 name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Decreased lung function

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the 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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Cataia Ives   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Karsta Luettich
  • Marja Talikka
  • Cataia Ives

Status

Provides 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. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. 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 Do not cite Under Development 1.51 Included in OECD Work Plan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 July 16, 2022 18:37

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

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. 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. 

AOP Development Strategy

Context

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. 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).

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

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 prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 941 Activation, EGFR Activation, EGFR
KE 914 Decrease, Apoptosis of ciliated epithelial cells Decreased ciliated cell apoptosis
KE 920 Occurrence, Metaplasia of goblet cells Goblet cell metaplasia
KE 923 Increase, Proliferation of goblet cells Increased goblet cell proliferation
KE 921 Occurrence, Hyperplasia of goblet cells Goblet cell hyperplasia
KE 1251 Chronic, Mucus hypersecretion Chronic, Mucus hypersecretion
KE 962 Increase, Mucin production Increase, Mucin production
AO 1250 Decrease, Lung function Decreased lung function

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes 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. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (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

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP 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. 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 sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. 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

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. 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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. 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.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  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)

Addressess 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. 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 of the literature that was cited for this AOP. More help

Allinson, J.P., Hardy, R., Donaldson, G.C., Shaheen, S.O., Kuh, D., and Wedzicha, J.A. (2016). The presence of chronic mucus hypersecretion across adult life in relation to chronic obstructive pulmonary disease development. Am. J. Respir. Crit. Care Med. 193, 662-672. 

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

Ayers, M., and Jeffery, P. (1988). Proliferation and differentiation in mammalian airway epithelium. Eur. Respir. J. 1, 58-80.

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

Burgel, P., and Nadel, J. (2004). Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 59, 992-996.

Caramori, G., Casolari, P., Di Gregorio, C., Saetta, M., Baraldo, S., Boschetto, P., et al. (2009). MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathol. 55, 321-331.

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., and 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.

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

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

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

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

Diaz-Guzman, E., and 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.

Eng, A., Mannetje, A.t., McLean, D., Ellison-Loschmann, L., Cheng, S., and Pearce, N. (2011). Gender differences in occupational exposure patterns. Occup. Environm. Med. 68, 888-894.

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.

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