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Relationship: 986

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, EGFR leads to Increase, Mucin production

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Activation, EGFR
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increase, Mucin production

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
EGFR Activation Leading to Decreased Lung Function adjacent High High Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Increased mucin production which leads to mucus hypersecretion in the airway epithelium is a key characteristic of many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (Yoshida and Tuder 2007). In airways, major gel-forming secreted mucins MUC5AC and MUC5B are produced in specialized mucin-producing goblet cells. Epidermal growth factor receptor (EGFR)-mediated signalling has been identified as the key pathway that leads to increased mucin production (Burgel and Nadel 2004). Following ligand binding in response to wide variety of stimuli (such as bacterial or viral infections, oxidative stress, particulate matter, etc) EGFR undergoes receptor dimerization and autophosphorylation resulting in activation of downstream pathways that lead to increase in mucin gene expression as well as result in increased number of goblet cells (Vallath et al. 2014). The increase in goblet cell numbers is out of the scope of this KER. As a result of EGFR signalling activation, mucin (MUC5AC, MUC5B) gene and protein expression is increased in airway epithelial cells leading to mucus overproduction and hypersecretion. The relationship between EGFR activation and downstream increase in mucin production is well established in studies of numerous laboratories, and interference with the EGFR signalling represents great pharmacological potential for treatment of airway mucus hyperproduction (Lai and Rogers 2010; Burgel and Nadel 2004).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The relevant research articles supporting this KER were identified using keywords: “EGFR” AND “mucin” or “mucus”, or “MUC5AC”, or “MUC5B”. The studies that did not demonstrate involvement of EGFR in the increase of the mucin production by blocking EGFR signalling (e.g., chemicals, antibodies) were omitted as weak evidence. Given the ample evidence in numerous papers, the compilation here does not claim to contain the exhaustive list of the studies, nonetheless presents convincingly strong data pool to substantiate the strength of the KER. EGFR-mediated increase in mucin production is also discussed in reviews (Burgel and Nadel 2004; Nadel 2001).

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

EGFR can be activated by bacterial infection, EGFR ligands, exposure to cigarette smoke and other sources of ROS, leading to increased mucin production via Ras/Raf-1/MEK/ERK-mediated activation of the Sp1 transcription factor, which can be suppressed at least partially in the presence of EGFR inhibitors (Sydlik et al., 2006; Casalino-Matsuda et al., 2006; Takeyama et al., 2008; Perrais et al., 2002; Hewson et al., 2004; Wu et al., 2007; Barbier et al., 2012; Lee et al., 2011).

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Numerous studies on different mammalian model systems conclusively demonstrate the positive role of EGFR activation in increased mucin expression. EGFR signalling upregulates the expression of mucin genes, such as MUC2 and MUC5AC, through activation of SP1 transcription factor (Y.C. Lee et al. 2011; Perrais et al. 2002). In addition, hypoxia inducible factor 1 subunit alpha (HIF1A) was also shown to be implicated in MUC5AC expression downstream of EGFR pathway (Yu, Li, et al. 2012). In one study, EGFR was shown to promote mucus production through antagonism with Claudin1 (Jia et al. 2021). Abundant evidence in studies from many laboratories suggests highly biologically plausible causal relationship between EGFR activation and increased mucin production.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

A study carried out in three airway epithelial cell systems (normal human bronchial epithelial primary culture, immortalized normal bronchial epithelial cell line HBE1, and human lung adenocarcinoma cell line A549) showed increased MUC5AC and MUC5B expression via SP1-mediated mechanism whereby MUC5AC expression was diminished by EGFR inhibition, but MUC5B expression was not sensitive to EGFR inhibition (Yuan-Chen Wu et al. 2007).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
  • Stimulation of EGFR by its ligands, 25 ng/ml EGF and 25 ng/ml TGFA, causes mucous glycoconjugate production in human pulmonary mucoepidermoid carcinoma cell line NCI-H292 (assessed by volume density of Alcian blue/periodic acid–Schiff (AB–PAS)). EGF and TGFA induce MUC5AC gene (Northern blot) and protein (ELISA) expression. Pretreatment of cells (30 min) with selective kinase inhibitors for EGFR (10 μg/ml BIBX1522, 10 μM AG1478, 10 μM Compound 56) prevented the ligand-induced staining for MUC5AC protein (Takeyama et al. 1999). Ovalbumin sensitization resulted in EGFR protein expression and mucous glycoconjugate production (AB-PAS-positive staining) in rat airways which was inhibited by pretreatment with EGFR inhibitor BIBX1522 (10 mg/kg, i.p.) (Takeyama et al. 1999). The same research group has demonstrated upregulation in EGFR-mediated MUC5AC mRNA and protein production after cigarette smoke exposure in NCI-H292 cells and in vivo in Sprague-Dawley rats (Takeyama et al. 2001).
  • IL13 treatment causes EGFR-dependent (diminished through EGFR-selective inhibitor BIBX1522 pretreatment) MUC5AC staining and AB/PAS-staining of mucous glycoconjugates in rat airway tissue. 50 ng IL-13 were necessary to significantly raise the % mucin-expressing epithelial area above background (<10% in controls vs 15% in treated rats), and % mucin-expressing epithelial area was maximal at the highest tested concentration, 500 ng. Mechanistically, IL13 induced TNF expression in airway epithelium and infiltrating neutrophils through IL8-like chemoattractant. TNF subsequently induced EGFR expression (Shim et al. 2001).
  • Instillation of agarose plugs (0.7- to 0.8-mm diameter 4% agarose type II medium electroendosmosis in PBS) on rat airways resulted in EGFR-dependent (diminished through EGFR-selective inhibitor BIBX1522 pretreatment) mucus glycoconjugate production and MUC5AC gene expression. Mechanistically, agarose plugs caused TNF release in the airway epithelium and inflammatory cells, thus inducing EGFR (H.M. Lee et al. 2000).
  • Daily treatment of primary human bronchial epithelial cells with 0.6 mM xanthine and 0.5 units xanthine oxidase for 3 days nearly doubled the levels of phosphorylated EGFR and increased expression of MUC5AC mRNA by approx. 2-fold and that of MUC5AC protein by ca. 30%. These responses could be at least partially prevented by pre-incubation with anti-EGFR antibodies and by tissue kallikrein (TK) inhibitor (TK processes pro-EGF) (Casalino-Matsuda, Monzón, and Forteza 2006).
  • MUC5AC and MUC5B gene and protein expressions were induced in Mycoplasma pneumoniae M129 infection in human NCI-H292 cells, primary human bronchial epithelial cells and mouse airways. EGFR phosphorylation and thus signalling was induced by M. pneumoniae, and EGFR inhibition (10uM AG1478) attenuated M. pneumonia-induced mucin overproduction (Hao et al. 2014).
  • Chronic treatment with EGFR inhibitor gefitinib (50 mg/kg, for 12 h each day, days 14-20) downregulated the expression of EGFR and markedly decreased the levels of MUC5AC (ELISA) in BALF of ovalbumin-challenged mice. The ovalbumin-induced mucus secretion (PAS staining) was significantly ablated by chronic gefitinib treatment in mouse lung tissue (Song et al. 2016).
  • TGFA increased MUC5AC protein production and the Alcian blue/PAS staining (mucous glycoconjugates) in NCI-H292 cells within 24 h, and pre-treatment with EGFR inhibitor AG1478 (10uM) prevented the increase in the staining and MUC5AC production (Takeyama et al. 2008).
  • Increased MUC5AC expression (ca. 5-fold) was seen in the tracheal, but not the lung epithelium of C57Bl/6 mice 48 h after instillation of PM2.5 (particulate matter with a diameter below 2.5 um). This effect was significant with 50 µg, but not with 10 µg PM2.5. PM2.5 dose-dependently increased MUC5AC expression in human H292 lung cancer cells and primary human bronchial epithelial cells grown as monolayer, with significant increases of ca. 10- and 8-fold above that of control at PM2.5 concentrations > 5 µg/cm2. At a concentration of 10 µg/cm2, MUC5AC mRNA level in H292 cells peaked at >30 times that of control after 24 h of treatment. When primary bronchial epithelial cells differentiated the air-liquid interface were treated with PM2.5, MUC5AC expression also increased in a dose-dependent manner. However, 10 µg/cm2 PM2.5 were necessary to induce a significant, maximal response (ca. 3-fold increase), and pretreatment with 10 µM AG1478 or 0.5 µg/µL neutralizing anti-EGFR antibody reduced this response by ca. 50% (Val et al. 2012).
  • Acrolein exposure of FVB/NJ mice at 2 ppm for 6 h per day, 5 days a week, for 4 weeks increased lung MUC5AC RNA and protein levels approx. 4-fold. Gavage of 100 mg/kg EGFR inhibitor erlotinib after every exposure abolished this effect (Deshmukh et al. 2008).
  • Infection of H292 cells with influenza A virus (IAV) at MOI=1 resulted in increased EGFR phosphorylation, peaking at 24 h. This was correlated with activation of ERK and Sp1 and increases in MUC5AC gene and protein levels. Cell treatment with anti-EGFR antibody or EGFR inhibitor PD168393 abolished MUC5AC increase. EGFR ligand TGFA neutralization with a specific antibody ablated IAV-induced MUC5AC up-regulation (Barbier et al. 2012).
  • Treatment of primary normal bronchial epithelial (NHBE) cells and HBE1 cell cultures with 10 nM TCDD resulted in increased MUC5AC gene and protein levels. EGFR, ERK, p38 MAPK phosphorylation was also increased. TCDD-induced MUC5AC expression was significantly decreased when cells were pretreated with EGFR inhibitor AG1478, MEK/ERK inhibitor PD98059, and p38 inhibitor SB203580. SP1 involvement was demonstrated by treatment with the Sp1 inhibitor mithramycin A (Y.C. Lee et al. 2011).
  • Treatment of NCI-H292 cells with EGFR ligands with EGF (25 ng/ml), TGFA (20 ng/ml), or TNF (40 ng/ml) resulted in increase of MUC2 and MUC5AC promoter activity, mRNA levels, and apomucin expression. Pretreatment with EGFR inhibitor AG1478 resulted in complete inhibition of MUC2 and MUC5AC gene up-regulation by EGF and TGFA. Mechanistically, EGF and TGFA-induced increases in MUC2 and MUC5AC were mediated by Sp1 on transcriptional level (Perrais et al. 2002).
  • Jia and colleagues demonstrated that EGFR activation promotes mucus production and exacerbates asthma in mice through Claudin1 (CLDN1) decrease (Jia et al. 2021). Claudin1 knockdown promoted MUC5AC gene and protein expression in human bronchial epithelial 16HBE cells, ALI cultures, and exacerbated house dust mite (HDM)-induced asthma in mice (notably, increased MUC5AC protein levels and mucus secretion). EGFR ligand HBEGF (heparin binding EGF like growth factor) significantly decreased mRNA levels of CLDN1 in 16HBE cells and promoted MUC5AC expression which was reversed by CLDN1 overexpression. EGFR inhibitor erlotinib restored the expression of CLDN1 and decreased MUC5AC levels and mucus secretion in the HDM-induced asthma model (Jia et al. 2021).
  • Virulence factor flagellin purified from human respiratory pathogen Pseudomonas aeruginosa increases MUC5AC mRNA and protein levels in a concentration-dependent manner reaching a peak at 10 ug/ml in 16HBE cells. Reactive oxygen species (involved in EGFR activation) scavenging, TGFA (EGFR ligand) neutralization with an antibody, TACE (metalloprotease involved in TGFA release) inhibition with TAPI-1, and treatment with EGFR neutralizing antibody which blocks EGFR ligand binding and inhibits EGFR phosphorylation, all decreased flagellin-induced MUC5AC production (Yu, Zhou, et al. 2012).
  • Blastomyces dermatitidis–infected canine and Histoplasma capsulatum–infected feline airway epithelia exhibited increased expression of mucins MUC5AC and MUC5B which was inversely correlated with expression of FOXA2. Similarly, B. dermatitidis increased mucins and reduced FOXA2 in immortalized canine airway carcinoma (BACA) cells. B. dermatitidis also increased phosphorylation levels of EGFR, AKT and ERK1/2 in BACA cells. Pretreatment of BACA cells with inhibitors of EGFR (AG1478), AKT (LY294002), and ERK1/2 (PD98059) before challenge by B. dermatitidis reduced expression of MUC5AC and MUC5B and restored the expression of FOXA2, indicating that pulmonary blastomycosis activates both EGFR-ERK1/2 and EGFR–AKT signalling pathways leading to FOXA2 suppression and excessive mucus production (Choi et al. 2021).
  • Treatment of primary human lobar bronchial epithelial cells (HLBECs) with pine wood smoke particulate matter (WSPM; 2.5 μm and smaller fractions) for 24 h induced MUC5AC expression 20–30-fold. MUC5AC protein levels in the cells and MUC5AC secretion into media was also increased after pine WSPM treatment. In addition, pine WSPM induced MUC5AC expression in mouse airways and in primary human small airway epithelial cells (SAECs), immortalized HBEC-3KT cells, as well as human airway epithelial cell models from unique donors. At 6 h after pine WSPM treatment, increased EGFR phosphorylation was observed in HLBECs. Transcript abundance of EGFR ligands EPGN and HB-EGF was increased up to approximately 20- and 2.5-fold, respectively, in 24 h following pine WSPM treatment. Inhibition of EGFR with 10 uM AG1478 prevented pine WSPM-induced MUC5AC expression. Inhibitor treatments of GSK3β (TWS119) and p38 MAPK (PD16936) also effectively inhibited WSPM-induced MUC5AC expression suggesting p38 MAPK and GSK3β implication downstream of EGFR (Memon et al. 2020).
  • Particulate matter (PM (50, 100, and 300 μg/cm3)) treatment of human bronchial epithelial cells (HBECs) over 24 h significantly and dose-dependently upregulated MUC5AC expression. PM also increased the levels of EGFR ligand Amphiregulin (AREG) as well as EGFR and AKT/ERK phosphorylation. AREG silencing through siRNA alleviated PM-induced EGFR (and AKT, ERK) phosphorylation and mucus hypersecretion in HBECs, while exogenous AREG enhanced PM-induced EGFR/AKT/ERK pathway activation and mucus hypersecretion. EGFR inhibitor AG1478 pretreatment significantly inhibited EGFR-AKT/ERK pathway activation and MUC5AC expression in PM-stimulated HBECs (Wang et al. 2019).
  • Yet another study on effect of wood smoke PM with a diameter less than 2.5um (WSPM2.5), show increase in MUC5AC production in the rat airways, primary human airway epithelial cells and the NCI-H292 cell line. EGFR-selective inhibitor AG1478 pretreatment prevented MUC5AC expression in NCI-H292 cells (Huang et al. 2017).
  • MUC5B and variably MUC5AC RNA levels were increased in both proximal and distal airways in COVID-19 autopsy lungs. MUC5B-dominated mucus accumulation was observed in bronchioles, microcysts, and in damaged lung alveolar spaces in 90% of COVID-19 subjects. In SARS-CoV-2-infected human bronchial epithelial (HBE) cultures MUC5B/MUC5AC gene expression peaked 7-14 days post inoculation, MUC5B protein levels were significantly up-regulated at day 14 and MUC5AC protein showed tendency of up-regulation. SARS-CoV-2 infection of HBE cultures induced expression of EGFR ligands (AREG, HBEGF). Inhibiting EGFR pathway with EGFR-tyrosine kinase inhibitor (Gefitinib) or with EGFR monoclonal antibody (Cetuximab) reduced SARS-CoV-2-induced MUC5B and MUC5AC gene expressions in HBE cultures (Kato et al. 2022).
  • LPS-induced increases in MUC5AC mRNA and protein levels and increased Alcian blue/PAS staining in rat nasal epithelium were significantly inhibited by EGFR inhibitor AG1478 intranasal instillation (Takezawa et al. 2016).
  • EGFR inhibitor AG1478 treatment of bronchial epithelial cell cultures from asthmatic children showed significant reductions in mucus (MUC5AC) secretion. In addition, bronchial epithelial cell cultures from asthmatic children differentiated in EGF-negative conditions had reduced mucus secretion compared to the cultures differentiated in the presence of EGF (Parker et al. 2015).
  • Treatment with 100 μg/mL of LPS for 24 h increased MUC5AC protein and phosphorylated EGFR levels in HIBECs. LPS-induced MUC5AC overexpression was significantly inhibited by treatment with 10 μg/mL of EGFR inhibitor AG1478 (Liu et al. 2013).
  • Cigarette smoke treatment (9 puffs) for 24 hours increased MUC5AC expression in 16HBE cells in a HIF1A-dependent manner. HIF1A knockdown with specific siRNA significantly inhibited cigarette smoke‐induced MUC5AC mRNA and protein increase. EGFR inhibitor gefitinib inhibited cigarette smoke‐induced HIF1A production and HIF1A activity, and decreased MUC5AC mRNA and protein levels in a concentration‐dependent manner (Yu, Li, et al. 2012).
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

In many studies the measurements of EGFR activity and mucin levels were routinely done simultaneously at same time points after stressor introduction. Several examples below demonstrate that various stressors or EGFR ligands increase mucin levels as early as 12 hour time-point, usually reaching higher levels of expression at later time-points such as 24 hours.

  • EGF (25 ng/ml) alone or TGFα (25 ng/ml) alone caused an ≈2-fold increase in MUC5AC protein production (ELISA) in NCI-H292 cells (routinely done 12 or 24 hours). Incubation with EGF or TGFα increased MUC5AC gene expression beginning at 12 h and reaching a maximum at 24 h (Takeyama et al. 1999).
  • IL13 treatment caused MUC5AC staining and Alcian blue-PAS -positive staining of mucous glycoconjugates in rat airway tissue after IL13 instillation. EGFR protein staining started to occur at 16h and increased at 24h. Similarly, AB/PAS staining was clearly detectable at 16h and reached higher levels at 24h (Shim et al. 2001).
  • Instillation of agarose plugs on rat airways resulted in EGFR-dependent mucus glycoconjugate production and MUC5AC gene expression detectable as early as 24 h and greatest 72 h after instillation. Authors also show a clearly detected immunostaining with an antibody to EGFR in cells that stained positively with AB/PAS (H.M. Lee et al. 2000).
  • M. pneumoniae M129 infection led to respectively 6.8- and 5-fold increase in mucins MUC5AC and MUC5B in NHBE cells after 18h of infection. In NCI-H292 cells exposure to M. pneumoniae M129 for 18h stimulated MUC5AC and MUC5B expressions to 2.9- and 3-fold, respectively.  Phosphorylated EGFR was also detected at the 18h postinfection in NCI-H292 cells. After 3 days of infection with M. pneumoniae, the conducting airways of mice displayed mucus hypersecretion with 8.8-fold higher expression of MUC5AC and 9.4-fold higher levels of MUC5B protein (Hao et al. 2014).
  • Infection of NCI-H292 cells with influenza A virus at MOI=1 resulted in increased EGFR phosphorylation (and related MUC5AC increase), peaking at 24 h (Barbier et al. 2012).
  • Treatment of NCI-H292 cells with EGF (25 ng/ml), TGFA (20 ng/ml), or TNF (40 ng/ml) resulted in EGFR-dependent increases of MUC2 and MUC5AC promoter activity, mRNA levels, and apomucin expression assessed at 24 hours (Perrais et al. 2002).
  • Daily intranasal insitillation of 0.1 mg LPS (E.coli 0111:B4) for 3 consecutive days increased rat nasal epithelium mucus production which was inhibited by intranasal instillation of 10 mg/kg AG1478 (Takezawa et al. 2016).

The following studies show that EGFR activation (upstream KE) occurs earlier than mucin expression (downstream KE), complying with temporal concordance terms of upstream KE occurring before downstream KE.

  • Treatment of NHBE cells with 10 nM TCDD resulted in significantly increased EGFR phosphorylation after 30 min. TCDD treatment led to a time-dependent increase in MUC5AC promoter activity, peaking between 6 and 12 h. The results demonstrate that TCDD activates EGFR within 30 minutes, activates downstream ERK and p38 within 3–4 hours, followed by Sp1 phosphorylation increase at 4–6 hours, leading to increase in MUC5AC transcription (Y.C. Lee et al. 2011).
  • At a concentration of 10 µg/cm2 PM2.5, MUC5AC mRNA level in NCI-H292 cells peaked at >30 times that of control after 24h of treatment and decreased to approx. 20-fold that of control at 36h; the increase after 8h time point was not significant. EGFR ligand AREG release was significantly induced by 10 µg/cm2 PM2.5 from 8h of exposure to 36h. AREG ligand was tested alone and shown to induce MUC5AC expression at concentrations found in the supernatants of PM2.5-treated cells after 24h exposure (Val et al. 2012).
  • Treatment of primary HLBECs with pine wood smoke particulate matter (WSPM) for 24 h induced MUC5AC expression 20–30-fold, earlier time-points were not tested. EGFR phosphorylation was already increased following pine WSPM treatment at 6 h (but not at 2 h). The mRNA expression of EGFR ligands EPGN and HB-EGF rapidly increased within 2–4 h of pine WSPM exposure, and HLBEC treatment with EPGN and HB-EGF induced MUC5AC expression, albeit to a lesser degree than pine WSPM (Memon et al. 2020).
  • HBEC treatment with particulate matter (PM) for 24 h significantly induced MUC5AC expression through EGFR/AKT/ERK pathway whereby EGFR phosphorylation increase was observed at 15 minutes after PM treatment and reached highest levels at 1 hour post-treatment. However, MUC5AC levels were not measured at earlier time-points (Wang et al. 2019).
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Wood smoke particulate matter with a diameter less than 2.5um (WSPM2.5) induced MUC5AC production in the rat airways, primary human airway epithelial cells and the NCI-H292 cell line. Mechanistic investigation in NCI-H292 cells showed that MUC5AC production occurs through amphiregulin (AREG)-EGFR-ERK signalling (a. AREG neutralization suppressed most of the WSPM2.5-induced EGFR and ERK phosphorylation, b. pretreatment with EGFR-selective inhibitor AG1478 abolished ERK activation and MUC5AC expression, c. ERK–selective inhibitor PD98059 pretreatment inhibited WSPM2.5-induced MUC5AC expression). In turn, AREG-EGFR-ERK pathway activation was shown to contribute to the de novo synthesis of AREG (a. pretreatment with AG1478 or PD98059 significantly reduced WSPM2.5-induced AREG mRNA expression and AREG release, b. exogenous AREG treatment increased AREG mRNA expression, an effect that was inhibited in the presence of AG1478 or PD98059). Thus this positive feedback loop sustains mucus production (Huang et al. 2017).  

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

EGFR activation leading to mucus hypersecretion was shown in human primary and cultured airway epithelial cell models (Casalino-Matsuda, Monzón, and Forteza 2006; Y.C. Lee et al. 2011; Takeyama et al. 1999; Val et al. 2012), in mouse (Deshmukh et al. 2008; Song et al. 2016), rat (H.M. Lee et al. 2000; Shim et al. 2001), canine and feline respiratory epithelium (Choi et al. 2021).

References

List of the literature that was cited for this KER description. More help

Barbier, D., I. Garcia-Verdugo, J. Pothlichet, R. Khazen, D. Descamps, K. Rousseau, D. Thornton, M. Si-Tahar, L. Touqui, M. Chignard, and J. M. Sallenave. 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 (2): 149-57. https://doi.org/10.1165/rcmb.2011-0405OC.

Burgel, P. R., and J. A. Nadel. 2004. "Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium." Thorax 59 (11): 992-6. https://doi.org/10.1136/thx.2003.018879.

Casalino-Matsuda, S. M., M. E. Monzón, and R. M. Forteza. 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 (5): 581-91. https://doi.org/10.1165/rcmb.2005-0386OC.

Choi, W., A. X. Yang, A. Sieve, S. H. Kuo, S. Mudalagiriyappa, M. Vieson, C. W. Maddox, S. G. Nanjappa, and G. W. Lau. 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 (1): 108-130. https://doi.org/10.1016/j.ajpath.2020.09.013.

Deshmukh, H. S., C. Shaver, L. M. Case, M. Dietsch, S. C. Wesselkamper, W. D. Hardie, T. R. Korfhagen, M. Corradi, J. A. Nadel, M. T. Borchers, and G. D. Leikauf. 2008. "Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production." Am J Respir Cell Mol Biol 38 (4): 446-54. https://doi.org/10.1165/rcmb.2006-0339OC.

Hao, Y., Z. Kuang, J. Jing, J. Miao, L. Y. Mei, R. J. Lee, S. Kim, S. Choe, D. C. Krause, and G. W. Lau. 2014. "Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins." Infect Immun 82 (12): 5246-55. https://doi.org/10.1128/iai.01989-14.

Huang, L., J. Pu, F. He, B. Liao, B. Hao, W. Hong, X. Ye, J. Chen, J. Zhao, S. Liu, J. Xu, B. Li, and P. Ran. 2017. "Positive feedback of the amphiregulin-EGFR-ERK pathway mediates PM2.5 from wood smoke-induced MUC5AC expression in epithelial cells." Sci Rep 7 (1): 11084. https://doi.org/10.1038/s41598-017-11541-1.

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