This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

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

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
Karsta Luettich   (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
  • Hasmik Yepiskoposyan

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help
  • Rex FitzGerald

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
Handbook Version OECD status OECD project
v1.0 Under Development 1.51
This AOP was last modified on April 29, 2023 16:02

Revision dates for related pages

Page Revision Date/Time
Activation, EGFR March 08, 2023 03:59
Increase, Mucin production March 09, 2023 01:55
Decrease, Lung function September 08, 2021 04:54
Increase, goblet cell number March 08, 2023 05:04
Activation, EGFR leads to Increase, goblet cell number March 16, 2023 04:09
Activation, EGFR leads to Increase, Mucin production March 09, 2023 05:26
Increase, goblet cell number leads to Increase, Mucin production March 17, 2023 09:30
Increase, Mucin production leads to Decreased lung function March 16, 2023 06:05
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

Increase in mucin production and consequent mucus hypersecretion in the airways are key attributes of many lung diseases, including asthma, cystic fibrosis and chronic bronchitis, all of which are characterized by decreased lung function (Yoshida and Tuder, 2007). Mucus hypersecretion is characterized by an increase in the number of goblet cells, mucin synthesis and mucus secretion which can result in airway obstruction and lung function decline (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 mucin production (Burgel and Nadel, 2008). This AOP for decreased lung function originates in 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 adverse outcome. The causal relationships in this AOP, including EGFR activation leading to increased number of mucin-producing goblet cells and to increased mucin production, are substantiated by multiple lines of evidence in studies performed using different model systems and approaches. Understanding how the inhaled toxicant-induced EGFR activation leads to pulmonary function impairment will be relevant to risk assessment of airborne pollutant 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

This AOP delineates a sequence of key events initiating with stressor-induced activation of EGFR and resulting in decreased lung function through increased production of mucins. Excessive mucin production and consequent mucus hypersecretion are characteristic features of chronic diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, chronic bronchitis, and asthma, 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). Mucus hypersecretion during the disease course can result in airway obstruction, decreased peak expiratory flow, respiratory muscle weakness, leading to decreased lung function (Kim and Criner, 2015, Yoshida and Tuder, 2007). Lung function decrease can have serious consequences and is associated with increased mortality (Panizza et al., 2006). This AOP is aimed to compile and organize the vast knowledge around molecular and cellular events and their relationships leading to lung function decrease with an overarching goal to facilitate the prediction and assessment of decreased pulmonary function. In vitro assays spanning from cell culture to organ system assays, with an aid of in silico methodology, all performed in human context, could be applied to measure each KE for inhaled toxicant assessments and adverse outcome predictions, and would contribute to eventual replacement of in-vivo tests in animals. This concept of hazard assessment and AO prediction aligns with integrated approach to testing and assessment (IATA) framework as a mechanistic support for regulatory decision-making (Clippinger et al., 2018). 

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

Chronic respiratory diseases such as COPD, cystic fibrosis, and asthma, characterized by increased mucin production and eventual lung function decrease, pose a substantial public health burden. EGFR-mediated signaling has been identified as the key pathway that leads to airway mucin production (Burgel and Nadel, 2004). Ligand binding in response to various toxicants and pathogens activates the EGFR tyrosine kinase on the surface of airway epithelial cells. Therefore, we determine the molecular initiating event (MIE) of this AOP the activation of EGFR which leads to adverse outcome (AO) of decreased lung function through key events (KE) increased mucin production and increased mucin-producing goblet cell numbers. In addition to increased mucin production, exposure-related decrease in lung function is also associated to ciliary function, the airway surface liquid height and mucociliary clearance efficiency, all of which are outlined and described in AOP411, AOP424, and AOP425. 

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 2117 Increase, goblet cell number Increase, goblet cell number
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
Unspecific

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 increased mucin production and decreased lung function is predominantly studied in adults; however, it has been shown to also occur in pediatric asthma and bronchitis (Parker et al., 2015, Rogers, 2003). 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 patient, cell culture and animal model biological systems. In vitro and in vivo studies in these systems have been performed to clarify the mechanisms of EGFR activation leading to mucus hyperproduction by studying the increase in goblet cells and upregulation in mucin transcript and protein expression. There are several clinical studies on mucus hypersecretion and how it affects lung function in humans with chronic bronchitis, asthma and other chronic lung diseases. The use of laboratory animals in human disease phenotype modelling enhances the understanding of disease mechanisms but also has limitations, e.g. due to anatomic differences between human and animal airways, differences in disease severity, difficulty of lung function measurements (Nikula and Green, 2000, Fricker et al., 2014). In summary, assembled data suggest that the KEs of this AOP are preserved across rodents and humans and there is good evidence supporting the occurrence of KERs in these species. 

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

MIE: EGFR activation 

EGFR signaling is considered critical for mucin production (Vallath et al., 2014). Large amount of studies indicate that activation of EGFR through stressors and receptor ligands increase goblet cell numbers and mucin production while inhibition of EGFR decreases mucin production or goblet cell numbers (Barbier et al., 2012, Casalino-Matsuda et al., 2006, Choi et al., 2021, Deshmukh et al., 2008, Hao et al., 2014, Huang et al., 2017, Jia et al., 2021, Kato et al., 2022, Lee et al., 2000, Lee et al., 2011, Memon et al., 2020, Parker et al., 2015, Perrais et al., 2002, Shim et al., 2001, Song et al., 2016, Takeyama et al., 1999, Takeyama et al., 2001, Takeyama et al., 2008, Takezawa et al., 2016, Tyner et al., 2006b, Val et al., 2012, Wang et al., 2019, Yu et al., 2012a, Yu et al., 2012b). As for downstream AO, several studies indicate positive correlation between EGFR pathway activation and lung function decrease (Singanayagam et al., 2022, Feng et al., 2019, Lin et al., 2021). Taken together, and considering the strong causal link of EGFR activation on adjacent KEs, we propose high essentiality for the MIE “Activation, EGFR” in the AOP148.  

KE: Increase, mucin production 

Increased airway mucin production is a necessary condition for mucus hypersecretion. The stressor exposure maintenance and goblet cell number increase are important for sustained mucin production increase, otherwise the mucus hypersecretion resolves following re-establishment of airway homeostasis by anti-inflammatory mechanisms (Rose and Voynow, 2006). Mucus hypersecretion is a key feature of many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis and chronic bronchitis, all of which are characterized by decreased lung function. Evidences from literature indicate that sustained increased mucin production with consequent mucus hypersecretion correlate with lung function decrease (Caramori et al., 2009, Innes et al., 2006, Vestbo and Rasmussen, 1989, Vestbo et al., 1996, Ramos et al., 2014). Overall, increased mucin production is necessary but not always sufficient for leading to downstream events. Given the requirement of the KE for AO to occur we suggest high essentiality for the KE “Increase, mucin production” in the AOP148. 

KE: Increase, goblet cell number 

Goblet cells are specialized cells for mucin expression. Following stressor exposure, goblet cell numbers can increase which provides capacity to increase mucin production. Increased goblet cell numbers which can result from goblet cell hyperplasia and/or metaplasia sustain airway mucin overproduction contributing to airway obstruction and consequent lung function decline (Rose and Voynow 2006). Several studies show positive correlation between increase in goblet cell number and decrease in lung fuction (Innes et al., 2006, Raju et al., 2016, Ma et al., 2005, Celly et al., 2006). Considering above-mentioned, we propose high essentiality for the KE “Increase, goblet cell number” in the AOP148. 

Evidence Assessment

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

Biological Plausibility

KER: EGFR activation leads to Increase, mucin production 

Large number of studies using EGFR-activating ligands and EGFR inhibitors consistently show causal link leading from EGFR activation to increased production of mucin proteins (Barbier et al., 2012, Casalino-Matsuda et al., 2006, Choi et al., 2021, Deshmukh et al., 2008, Hao et al., 2014, Huang et al., 2017, Jia et al., 2021, Kato et al., 2022, Lee et al., 2000, Lee et al., 2011, Liu et al., 2013, Memon et al., 2020, Parker et al., 2015, Perrais et al., 2002, Shim et al., 2001, Song et al., 2016, Takeyama et al., 1999, Takeyama et al., 2001, Takeyama et al., 2008, Takezawa et al., 2016, Val et al., 2012, Wang et al., 2019, Yu et al., 2012a, Yu et al., 2012b). EGFR activation as a leading pathway for increased mucin production has broad acceptance in the scientific community and has been discussed also in review articles (Burgel and Nadel, 2004, Lai and Rogers, 2010). Therefore, we propose high biological plausibility for this KER. 

KER: EGFR activation leads to Increase, goblet cell number 

EGFR ligands and variety of stressors such as oxidative stress, cigarette smoke, allergens, viruses and bacterial endotoxins increase goblet cell number in an EGFR-dependent manner (Casalino-Matsuda et al., 2006, Gu et al., 2008, Hirota et al., 2012, Jia et al., 2021, Parker et al., 2015, Shatos et al., 2008, Song et al., 2016, Takeyama et al., 1999, Takeyama et al., 2001, Takezawa et al., 2016, Tyner et al., 2006a). Given the strong empirical evidence for involvement of EGFR in regulating the number of goblet cells and high reproducibility demonstrated in both in vitro and in vivo studies, we suggest high biological plausibility for this KER. 

KER: Increase, goblet cell number leads to Increase, mucin production 

Goblet cells are specialized cells for mucin production. The increase in the number of goblet cells is needed to accommodate the increased need for mucin production indicating that this KER is an inferred relationship, i.e. the occurrence of the downstream KE is inferred from the fact of occurrence of the upstream KE. Many studies demonstrate the correlation between increase in goblet cell numbers and mucin production (Zuhdi Alimam et al., 2000, Takezawa et al., 2016, Hao et al., 2012, Innes et al., 2006, Liang et al., 2017, Lee et al., 2000, Casalino-Matsuda et al., 2006, Tyner et al., 2006b), in fact the accepted measure of goblet cell number increase is the enhanced staining for mucus in the tissues. Thus, we judge the KER as highly plausible. 

KER: Increase, mucin production leads to Decrease, lung function 

Increased mucus production and hypersecretion is a physiological response to harmful exposures. This response is typically of short duration and does not pose a major problem to normal lung function. However, in the presence of sustained mucus production and secretion, maintained and promoted through increased number of mucin producing goblet cells, airways can become obstructed and result in lung function decline. In addition, impaired mucociliary clearance contributes to airway obstruction (Whitsett, 2018) and it is currently unclear whether chronic mucus hypersecretion alone is sufficient to elicit a decrease in lung function. Clinical studies and model animal research showed that MUC5AC production was inversely correlated with parameters of lung function (FEV1 (% predicted), FEV1/FVC ratio, inspiratory capacity) (Caramori et al., 2009, Innes et al., 2006, Raju et al., 2016), and epidemiological evidence indicates a link between mucus hypersecretion and decreased lung function (Allinson et al., 2016, Pistelli et al., 2003, Vestbo et al., 1996). As a cause-effect relationship cannot be conclusively proven, we suggest moderate biological plausibility for this KER. 

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
Modulating Factor (MF) Influence or Outcome KER(s) involved
Mucociliary clearance (MCC) Impaired MCC contributes to decreased lung function (AOPs 411, 424, 425) Increase, mucin production leads to Decrease, lung function

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 and goblet cell number increase. In the majority of these studies, the summary evidence indicates dose-response relationships, time-response relationships, and causality for EGFR activation leading adjacent downstream KEs, lending strong support for these KERs. However, data for increased mucin production and mucus hypersecretion leading to lung function decline 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 lung diseases, such as COPD, chronic bronchitis and asthma. 

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 function for 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, means for early identification of potentially hazardous exposures are critical for the development of appropriate public health interventions. The AOP could provide a framework for mapping out suitable in vitro models and tests for evaluation of distinct KEs in different exposure contexts thus contributing to eventual replacement of in-vivo tests in animals. The predictive power of AOP aligns well with IATA framework to integrate diverse sources of information as a mechanistic support on chemical hazard characterization. 

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. & 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, 662-72. 

BARBIER, D., GARCIA-VERDUGO, I., POTHLICHET, J., KHAZEN, R., DESCAMPS, D., ROUSSEAU, K., THORNTON, D., SI-TAHAR, M., TOUQUI, L., CHIGNARD, M. & SALLENAVE, J. M. 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, 149-57. 

BURGEL, P. & NADEL, J. 2004. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax, 59, 992-996. 

BURGEL, P.-R. & NADEL, J. A. 2008. Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. European Respiratory Journal, 32, 1068-1081. 

CARAMORI, G., CASOLARI, P., DI GREGORIO, C., SAETTA, M., BARALDO, S., BOSCHETTO, P., ITO, K., FABBRI, L. M., BARNES, P. J., ADCOCK, I. M., CAVALLESCO, G., CHUNG, K. F. & PAPI, A. 2009. MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathology, 55, 321-31. 

CASALINO-MATSUDA, S. M., MONZÓN, M. E. & 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, 581-91. 

CELLY, C. S., HOUSE, A., SEHRING, S. J., ZHANG, X. Y., JONES, H., HEY, J. A., EGAN, R. W. & CHAPMAN, R. W. 2006. Temporal profile of forced expiratory lung function in allergen-challenged Brown-Norway rats. Eur J Pharmacol, 540, 147-54. 

CHOI, W., YANG, A. X., SIEVE, A., KUO, S. H., MUDALAGIRIYAPPA, S., VIESON, M., MADDOX, C. W., NANJAPPA, S. G. & LAU, G. W. 2021. Pulmonary Mycosis Drives Forkhead Box Protein A2 Degradation and Mucus Hypersecretion through Activation of the Spleen Tyrosine Kinase-Epidermal Growth Factor Receptor-AKT/Extracellular Signal-Regulated Kinase 1/2 Signaling. Am J Pathol, 191, 108-130. 

CLIPPINGER, A. J., ALLEN, D., BEHRSING, H., BÉRUBÉ, K. A., BOLGER, M. B., CASEY, W., DELORME, M., GAÇA, M., GEHEN, S. C., GLOVER, K., HAYDEN, P., HINDERLITER, P., HOTCHKISS, J. A., ISKANDAR, A., KEYSER, B., LUETTICH, K., MA-HOCK, L., MAIONE, A. G., MAKENA, P., MELBOURNE, J., MILCHAK, L., NG, S. P., PAINI, A., PAGE, K., PATLEWICZ, G., PRIETO, P., RAABE, H., REINKE, E. N., ROPER, C., ROSE, J., SHARMA, M., SPOO, W., THORNE, P. S., WILSON, D. M. & JARABEK, A. M. 2018. Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity. Toxicol In Vitro, 52, 131-145. 

DESHMUKH, H. S., SHAVER, C., CASE, L. M., DIETSCH, M., WESSELKAMPER, S. C., HARDIE, W. D., KORFHAGEN, T. R., CORRADI, M., NADEL, J. A., BORCHERS, M. T. & LEIKAUF, G. D. 2008. Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am J Respir Cell Mol Biol, 38, 446-54. 

FENG, F., DU, J., MENG, Y., GUO, F. & FENG, C. 2019. Louqin Zhisou Decoction Inhibits Mucus Hypersecretion for Acute Exacerbation of Chronic Obstructive Pulmonary Disease Rats by Suppressing EGFR-PI3K-AKT Signaling Pathway and Restoring Th17/Treg Balance. Evid Based Complement Alternat Med, 2019, 6471815. 

FRICKER, M., DEANE, A. & HANSBRO, P. M. 2014. Animal models of chronic obstructive pulmonary disease. Expert Opin Drug Discov, 9, 629-45. 

GU, J., CHEN, L., SHATOS, M. A., RIOS, J. D., GULATI, A., HODGES, R. R. & DARTT, D. A. 2008. Presence of EGF growth factor ligands and their effects on cultured rat conjunctival goblet cell proliferation. Exp Eye Res, 86, 322-34. 

HAO, Y., KUANG, Z., JING, J., MIAO, J., MEI, L. Y., LEE, R. J., KIM, S., CHOE, S., KRAUSE, D. C. & LAU, G. W. 2014. Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins. Infect Immun, 82, 5246-55. 

HAO, Y., KUANG, Z., WALLING, B. E., BHATIA, S., SIVAGURU, M., CHEN, Y., GASKINS, H. R. & LAU, G. W. 2012. Pseudomonas aeruginosa pyocyanin causes airway goblet cell hyperplasia and metaplasia and mucus hypersecretion by inactivating the transcriptional factor FoxA2. Cell Microbiol, 14, 401-15. 

HIROTA, N., RISSE, P. A., NOVALI, M., MCGOVERN, T., AL-ALWAN, L., MCCUAIG, S., PROUD, D., HAYDEN, P., HAMID, Q. & MARTIN, J. G. 2012. Histamine may induce airway remodeling through release of epidermal growth factor receptor ligands from bronchial epithelial cells. Faseb j, 26, 1704-16. 

HUANG, L., PU, J., HE, F., LIAO, B., HAO, B., HONG, W., YE, X., CHEN, J., ZHAO, J., LIU, S., XU, J., LI, B. & RAN, P. 2017. Positive feedback of the amphiregulin-EGFR-ERK pathway mediates PM2.5 from wood smoke-induced MUC5AC expression in epithelial cells. Sci Rep, 7, 11084. 

INNES, A. L., WOODRUFF, P. G., FERRANDO, R. E., DONNELLY, S., DOLGANOV, G. M., LAZARUS, S. C. & FAHY, J. V. 2006. Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest, 130, 1102-8. 

JIA, Z., BAO, K., WEI, P., YU, X., ZHANG, Y., WANG, X., WANG, X., YAO, L., LI, L., WU, P., YUAN, W., WANG, S., ZHENG, J., HUA, Y. & HONG, M. 2021. EGFR activation-induced decreases in claudin1 promote MUC5AC expression and exacerbate asthma in mice. Mucosal Immunol, 14, 125-134. 

KATO, T., ASAKURA, T., EDWARDS, C. E., DANG, H., MIKAMI, Y., OKUDA, K., CHEN, G., SUN, L., GILMORE, R. C., HAWKINS, P., DE LA CRUZ, G., COOLEY, M. R., BAILEY, A. B., HEWITT, S. M., CHERTOW, D. S., BORCZUK, A. C., SALVATORE, S., MARTINEZ, F. J., THORNE, L. B., ASKIN, F. B., EHRE, C., RANDELL, S. H., O'NEAL, W. K., BARIC, R. S. & BOUCHER, R. C. 2022. Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease. Am J Respir Crit Care Med. 

KIM, V. & CRINER, G. J. 2015. The chronic bronchitis phenotype in chronic obstructive pulmonary disease: features and implications. Current Opinions in Pulmonary Medicine, 21, 133-141. 

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