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Philip Morris International: Karsta Luettich (Karsta.Luettich@pmi.com); Marja Talikka; Julia Hoeng
British American Tobacco: Frazer Lowe; Linsey Haswell; Marianna Gaca
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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 (KE1) 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) (KE2: Decreased Apoptosis of Ciliated Epithelial Cells). 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) (KE3: Transdifferentiation of ciliated epithelial cells). 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 (KE4: Increased Proliferation of Epithelial Cells) or Sp-1 transcription factor-mediated mucin gene and protein expression (KE5: Sp-1 Activation, KE6: Increase in Mucin Production,). Together these processes ultimately lead to goblet cell hyperplasia/metaplasia (GCH/GCM) (KE7: GCH, KE8: GCM) and mucus hypersecretion (Rogers, 2007) (KE9: Mucus Hypersecretion). 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 (AO: Decreased Lung Function) (Kim & Criner, 2015).
Summary of the AOP
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Molecular Initiating Event
|Molecular Initiating Event||Support for Essentiality|
|Lung function, Decrease|
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.
EGFR activation leading to mucus hypersecretion is predominantly studied in adults, however it has been shown to occur in pediatric asthma and bronchitis (Rogers, 2003; Parker et al., 2015). However, 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).
There are extensive studies on mucus hypersecretion in humans from a clinical perspective. In vitro and in vivo mouse, rat and human studies have been performed to clarify the mechanisms of EGFR involvement in mucus hypersecretion by studying the increase in goblet cells and subsequent mucus production.
There are no sex-specific differences in this AOP.
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.
EGFR signaling is considered critical for mucus hypersecretion and goblet cell hyperplasia (GCH)/goblet cell metaplasia (GCM)(Curran and 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 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). 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.
Weight of Evidence Summary
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
File:Mucus hypersecretion empirical support concordance table.pdf (Published studies investigating dose and time response to various KEs)
|Support for Biological Plausibility of KERs||Defining Question||High (Strong)||Moderate||Low (Weak)|
|Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?||Extensive understanding of the KER based on previous documentation and broad acceptance.||KER is plausible based on analogy to,accepted biological relationships, but scientific understanding is incomplete.||Empirical support for association between KEs, but the structural or functional relationship between them is not understood.|
|EGFR, Activation Indirectly Leads to Mucin Production, Increase:||Strong||Multiple studies show that EGFR activation leads to increased goblet cell numbers and mucin production, in rat studies via ligand-independent neutrophil activity through release of ROS (Shim et al., 2001), and TNF (Lee et al., 2000) and in normal human bronchial epithelial cells (NHBE) air liquid interface studies through ROS (Casalino-Matsuda et al., 2006), (Hao et al., 2014), and in a human pulmonary mucoepidermoid carcinoma cell line (NCI-H292) via EGFR ligands (Takeyama et al., 2008), (Takeyama et al., 1999).|
|EGFR, Activation Directly Leads to Proliferation of goblet cells, Increase||Moderate||Although there are no studies examining proliferation on goblet cells in the lung following EGFR activation, there is direct evidence in cultured conjunctival goblet cells (Gu et al., 2008), (Shatos et al., 2003). T|
|EGFR, Activation Directly Leads to Apoptosis of ciliated epithelial cells, Decrease||Moderate||One mouse study has shown that blocking EGFR in mouse trachea epithelial cells increased apoptosis in non-goblet cells (Tyner et al., 2006). It is moderately plausible that these non-goblet cells undergoing apoptosis due to EGFR blockade were ciliated cells, considering that in mouse, ciliated cells made up 45% of the cells (Tyner et al., 2006). Other studies looking generally at epithelial cell apoptosis showed that EGFR inhibition induced apoptosis in response to ROS in human airway epithelial cells (Casalino-Matsuda et al., 2006), ultrafine particles in rat lung epithelial cells (Sydlik et al., 2006) and TGFA in human airway cells (Takeyama et al., 2008).|
|EGFR, Activation Directly Leads to Transdifferentiation of ciliated epithelial cells, Increase||Moderate|| Two studies have shown EGFR involvement in a decrease in goblet cells and increase in ciliated cells via IL13-induced TGFA (Yoshisue and Hasegawa, 2004) or ROS-induced EGF (Casalino-Matsuda et al., 2006). A number of studies have shown ciliated cell transdifferentiation in response to IL13, in a mouse viral infection model and cultured mouse tracheal epithelial cells (Tyner et al., 2006), human nasal epithelium cells (Laoukili et al., 2001), 3D human airway epithelial model (Gomperts et al., 2007), and human bronchial epithelial cells (Turner et al., 2011). IL13 could be acting through EGFR, however it is possible that it could be acting through EGFR-independent pathways.
It is not well known how ciliated cell transdifferentiation occurs in humans. Under normal conditions, lung epithelial cells (except basal cells) are terminally differentiated, including ciliated cells (Rawlins and Hogan, 2008), and also in response to napthalene or sulfur dioxide-induced injury (Rawlins et al., 2006). However other studies showed that napthalene-induced injury can result in transdifferentiation of ciliated cells (Park et al., 2006).
|EGFR, Activation Directly Leads to SP1, Activation||Strong||SP1-mediated mucin gene expression following EGFR activation is well-documented. EGFR ligand interactions increase SP1 activity which increases mucin gene expression in human airway cells (Perrais et al., 2002). Other studies demonstrate EGF activation of SP1 to induce the expression of different genes in a variety of tissues (Merchant et al., 1995), (Zheng et al., 2001), (Ikari et al., 2009), (Lu et al., 2010). Although there is only one study that directly shows EGFR activation of SP1 to induce mucin gene expression, many studies in human lung epithelial cells show that perturbations that activate EGFR and mucin genes correlate with SP1 activation such as phorbol 12-myristate 13-acetate (PMA) (Hewson et al., 2004), (Wu et al., 2007), 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (Lee et al., 2011) and Influenza A virus (Barbier et al., 2012).|
|Proliferation of goblet cells, Increase Directly Leads to Hyperplasia of goblet cells, Increase||Strong||By definition, hyperplasia is increased cell production in a normal tissue or organ, therefore, goblet cell hyperplasia is an increase in the number of goblet cells.|
|Apoptosis of ciliated epithelial cells, Decrease Directly Leads to Transdifferentiation of ciliated epithelial cells, Increase||Moderate||Although this KER has not been proven experimentally and is a proposed theory (Tyner et al., 2006), (Curran and Cohn, 2010), it logically follows that an increase in ciliated cells due to decreased apoptosis allows for a larger pool of ciliated cells that can transdifferentiate into goblet cells.|
|Transdifferentiation of ciliated epithelial cells, Increase Directly Leads to Metaplasia of goblet cells, Increase||Strong||Metaplasia logically follows transdifferentiation as it is defined by the “phenotypic change” or “abnormal transformation of adult, fully differentiated tissue of one kind into a differentiation tissue of another kind” (Harkema and Hotchkiss, 1993). (Harkema and Wagner, 2002). Studies have found low mitotic rates along with increased number of goblet cells in airways, suggesting that differentiation into goblet cells is occurring rather than goblet cell proliferation (Shimizu et al., 1996), (Lamb and Reid, 1968).|
|SP1, Activation Directly Leads to Mucin production, Increase||Strong||Multiple studies have shown that there are SP1 binding sites in mucin gene promoters, including those of the MUC5AC, MUC5B and MUC2 genes, which are required for inducing mucin gene expression in NCI-H292 cells (Perrais et al., 2002), (Hewson et al., 2004), (Barbier et al., 2012) and primary human bronchial epithelial cells (Lee et al., 2011), (Wu et al., 2007).|
|Hyperplasia of goblet cells, Increase Directly Leads to Mucus hypersecretion||Moderate||An increased number of goblet cells in hyperplastic tissue can lead to mucus hypersecretion. Several studies show a correlation of hyperplasia and hypersecretion in rats in response to SO2 inhalation (Xu et al., 2000) and tobacco smoke (Coles et al., 1979). However, in these studies it was not confirmed that hyperplasia resulted from increased proliferation of goblet cells and hypersecretion could have been caused by goblet cell metaplasia. Studies have found low mitotic rates along with increased number of goblet cells in airways, suggesting differentiation into and not proliferation of goblet cells is occurring (Shimizu et al., 1996), (Lamb and Reid, 1968).|
|Metaplasia of goblet cells, Increase Directly Leads to Mucus hypersecretion||Strong||Goblet cell metaplasia occurs when ciliated cells transdifferentiate into goblet cells, effecively increasing the number of mucus-producing cells in the airway epithelium. There is an inverse relationship between goblet cell metaplasia and FEV1, a measure of lung function (Nagai et al., 1995). Smokers have an increased number of goblet cells in peripheral airways which is negatively correlated with low FEV1/FVC (lung function) which could be caused by mucus hypersecretion (Saetta et al., 2000). Studies have found low mitotic rates along with increased numbers of goblet cells in airways, suggesting differentiation into and not proliferation of goblet cells is occurring (Shimizu et al., 1996; Lamb and Reid, 1968).|
|Mucin production, Increase Directly Leads to Mucus, Hypersecretion||Strong||Mucus production can be stimulated by a variety of stimuli known to induce mucus hypersecretion including cigarette smoke or other oxidants (Shao et al., 2004), (Takeyama et al., 2001), (Yu et al., 2011), (Casalino-Matsuda et al., 2009), including phorbol 12-myristate 13-acetate (PMA), 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and sulfur dioxide (Hewson et al., 2004), (Lee et al., 2011), (Lamb and Reid, 1968) as well as bacteria (Dohrman et al., 1998; Hao et al., 2014).|
|Empirical Support for KERs||Defining Question||High (Strong)||Moderate||Low (Weak)|
|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?||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.||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|
|EGFR, Activation Indirectly Leads to Mucin Production, Increase||Strong||Studies show a dose-dependent increase in mucin production in response to EGFR activation by IL13 or infection (Shim et al., 2001), (Hao et al., 2014). Dose-response concordance is shown with infection inducing MIE EGFR 5-fold while inducing downstream KE mucin production 2-fold (Hao et al., 2014).|
|EGFR, Activation Directly Leads to Proliferation of goblet cells, Increase||Weak||Studies specific to goblet cells have been performed in cultured rat conjunctival goblet cells where EGFR ligands EGF, TGFA, HB-EGF stimulate an increase in phosphorylated EGFR as well as proliferation (Gu et al., 2008) and in human cultured conjunctival goblet cells where EGF caused a dose-dependent increase in proliferation (Shatos et al., 2003). In lung, studies either look generally at epithelial cell proliferation, not specifically goblet cells, or measure an increase in goblet cells, not specifically proliferation (Casalino-Matsuda et al., 2006). IL13-induced epithelial cell proliferation is increasingly inhibited with increasing EGFR inhibitor dose in mouse and human airway epithelial cells (Taniguchi et al., 2011), (Booth et al., 2001), (Booth et al., 2007). Proliferation of rat lung epithelial cells increases dose dependently with ultrafine particles, with upstream KE EGFR activation occurring at 2 hours while downstream KE proliferation occurs at 24 hours. (Sydlik et al., 2006). Although these studies do not specifically study goblet cells, epithelial cells can include goblet cells.|
|EGFR, Activation Directly Leads to Apoptosis of ciliated epithelial cells, Decrease||Weak||Apoptosis was shown to increase with EGFR inhibition in mouse epithelial non-goblet cells, correlating with an EGFR inhibitor dose-dependent decrease in beta-tubulin cells (Tyner et al., 2006). Studies have shown a decrease in ciliated cells (Gomperts et al. 2007) or ciliary beat frequency (Laoukili et al., 2001) with increased dose of IL13 or EGFR activation. Because this relationship is not specifically proven to be causal and there are no studies looking at multiple KEs in response to a perturbation, the empirical support showing ciliated cell apoptosis is weak.|
|EGFR, Activation Directly Leads to Transdifferentiation of ciliated epithelial cells, Increase||Moderate||One study has shown both an increase in goblet cells and decrease in ciliated cells (Turner 2011) and this is thought to be indicative of transdifferentiation. Overall, the empirical support for this KER is moderate.|
|EGFR, Activation Directly Leads to SP1, Activation||Weak||There is weak empirical support for EGFR activation of SP1. One study shows EGFR ligands induce mucin promoter activity which is decreased by half by addition of the SP1 inhibitor mithramycin A (Lee et al., 2011). There are no dose or time studies.|
|Proliferation of goblet cells, Increase Directly Leads to Hyperplasia of goblet cells, Increase||Weak||There is no empirical support as the KEs are equivalent in definition but on different levels of biological organization. Studies often study either the cellular or the tissue level but not the overlap.|
|Apoptosis of ciliated epithelial cells, Decrease Directly Leads to Transdifferentiation of ciliated epithelial cells, Increase||Weak||There is no empirical support for this KER.|
|Transdifferentiation of ciliated epithelial cells, Increase Directly Leads to Metaplasia of goblet cells, Increase||Weak||There is no empirical support as the KEs transdifferentiation and metaplasia are equivalent in definition but represent different levels of biological organization (cellular vs tissue level). Studies often study either transdifferentiation in cells or metaplasia in a tissue but not the overlap.|
|SP1, Activation Directly Leads to Mucin production, Increase||Strong||MUC5AC and MUC5B promoter activities are reduced by addition of SP1 inhibitor mithramycin A in a dose-dependent manner (Hewson et al., 2004; Lee et al., 2011; Wu et al., 2007). Upstream EGFR activation increased at an earlier time point, downstream SP1 activation was increased later and further downstream MUC5AC expression even later, however all KEs were not measured at all time points so time concordance cannot been confirmed (Lee 2011).|
|Hyperplasia of goblet cells, Increase Directly Leads to Mucus hypersecretion||Weak||There is no empirical support since clinical studies do not investigate both proliferating goblet cells/increased mucus and functional measures of mucus hypersecretion within the same study.|
|Metaplasia of goblet cells, Increase Directly Leads to Mucus hypersecretion||Weak||There is no empirical support since clinical studies do not investigate cellular differentiation into goblet cells and functional measures of mucus hypersecretion within the same study.|
|Mucin production, Increase Directly Leads to Mucus, Hypersecretion||Weak||There is no empirical support for this KER since mucus hypersecretion is measured by increased mucus production and therefore this KER is inherent in the definition of mucus hypersecretion.|
File:Mucus hypersecretion empirical support concordance table.pdf (Published studies investigating dose and time response to various KEs)
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.
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)
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.
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