This AOP is licensed under a Creative Commons Attribution 4.0 International License.
EGFR Activation Leading to Decreased Lung Function
Point of Contact
- Karsta Luettich
- Marja Talikka
|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 Do not cite||Under Development||1.51||Included in OECD Work Plan|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
|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|
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.
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
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|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)
|Activation, EGFR leads to Decreased ciliated cell apoptosis||adjacent||Moderate||Low|
|Decreased ciliated cell apoptosis leads to Goblet cell metaplasia||adjacent||Moderate||Low|
|Activation, EGFR leads to Goblet cell metaplasia||adjacent||High||Moderate|
|Goblet cell metaplasia leads to Chronic, Mucus hypersecretion||adjacent||Moderate||Moderate|
|Activation, EGFR leads to Increased goblet cell proliferation||adjacent||Moderate||Low|
|Increased goblet cell proliferation leads to Goblet cell hyperplasia||adjacent||High||Low|
|Goblet cell hyperplasia leads to Chronic, Mucus hypersecretion||adjacent||Moderate||Moderate|
|Increase, Mucin production leads to Chronic, Mucus hypersecretion||adjacent||High||Moderate|
|Chronic, Mucus hypersecretion leads to Decreased lung function||adjacent||High||Moderate|
|Activation, EGFR leads to Increase, Mucin production||non-adjacent||High||High|
|Reactive oxygen species||High|
Life Stage Applicability
Overall Assessment of the AOP
Domain of 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).
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).
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
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.
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.
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)
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.
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