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Increase, goblet cell number leads to Increase, Mucin production
Key Event Relationship Overview
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||Moderate||Karsta Luettich (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
|Not Otherwise Specified|
Key Event Relationship Description
An increase in goblet cell numbers arises from proliferation of this particular cell population (goblet cell hyperplasia) and/or from transdifferentiation of other specialized cell types, such as ciliated cells and club cells, into goblet cells (goblet cell metaplasia; Reader et al, 2003; Evans et al., 2004; Tesfaigzi, 2006). Goblet cell hyperplasia (GCH) is a common feature of airway epithelia in asthma and other respiratory diseases and can arise from airway injury following exposure to, for example, allergens, pathogens, or cigarette smoke (Miyabara et al., 1998; Nagao et al., 2003; Saetta et al., 2000; Walter et al., 2002; Hao et al., 2012, 2013, 2014; Lukacs et al., 2010; Yageta et al., 2014; Hegab et al., 2007; Silva and Bercik, 2012; Kim et al., 2016). Goblet cell metaplasia (GCM) is a key feature of remodeled airways observed in both asthma and chronic obstructive pulmonary disease (COPD; Kato et al., 2020; Kuchibhotla and Heijink, 2020; Nie et al., 2012). Since goblet cells are mucin-producing cells, an increase in goblet cell numbers will consequently lead to an increase (from basal levels) in mucin production, in fact methods for goblet cell detection and quantification include measurement of mucin levels with specific antibodies or staining of mucous glycoconjugates (Alcian Blue/periodic acid Schiff (AB/PAS) stain). Correlation and co-incidence between increase in goblet cell numbers and increased mucin production is shown in multiple studies.
Evidence Collection Strategy
The relevant research articles supporting this KER were identified using keywords: “goblet“ AND “mucin” or “mucus” or “MUC5AC”. Referenced articles within retrieved studies and reviews were also consulted. Not all retrieved articles were included as a support for this KER since they generally repeat the same conclusions listed in the evidence texts below.
Evidence Supporting this KER
This KER is inferred in that goblet cells are specialized mucin production cells and widely accepted measurement methods for counting goblet cells are based on staining of mucous glycoconjugates. There is indirect evidence demonstrating an increase in mucin production along the presence of GCH or GCM in airway epithelia following stressor exposures, judged by increased MUC5AC mRNA and protein expression, histopathological examination, increase in AB/PAS staining, and/or MUC5AC-positive antibody staining (Alimam et al, 2000; Hegab et al., 2007; An et al., 2013; Zhou et al., 2016). Increase in goblet cell number and mucin overproduction are also linked experimentally through genetic modification. For example, conditional deletion of transcription factor Foxa2 in respiratory epithelial cells of the developing mouse lung results in goblet cell hyperplasia in bronchi and bronchioles at post-natal day 16 and later (evidenced by histology), which was accompanied by extensive AB/PAS and MUC5AC staining (Wan et al., 2004). Similarly, Muc1-knockout rats exposed to cigarette smoke were protected from goblet cell metaplasia and MUC5AC overproduction (Kato et al., 2020).
This KER is inferred from the functional characteristic of the goblet cells whose primary role is mucin production, hence the assumption that increase in goblet cell numbers also increases mucin production is highly plausible. Studies in human cells, mice and rats demonstrate that mucin content or MUC5AC mRNA and protein expression increase in the presence of histologically confirmed GCH or GCM. While both events are measured in parallel and causal evidence is missing, our confidence remains high for the plausibility of this relationship.
Uncertainties and Inconsistencies
MUC5B, mainly present in submucosal glands, is the other main mucin found in human airways (Rose and Voynow, 2002). MUC5AC and MUC5B often both increase with goblet cell numbers increase in patients with respiratory diseases (Burgel et al., 200). However, depending on the causative agent, dominant MUC5B immunophenotypes are observed with no induction in MUC5AC (Silva and Bercik, 2012). Sprague-Dawley rats receiving one intratracheal dose of LPS developed GCH in their terminal bronchioles that was not MUC5AC and PAS-positive. An analysis in human bronchus epithelial cells confirmed that when challenged with supernatant from LPS-stimulated macrophages, goblet cells induced MUC5B levels but MUC5AC was inhibited.
Known modulating factors
The following examples all describe the parallel increase in goblets cells and mucin production after exposure to a noxious agent. In some of these examples, the response-response relationship is reinforced by the use of an antagonist or inhibitor treatment that attenuates or blocks the stressor-induced goblet cell proliferation and concomitantly reduces mucin mRNA and protein expression.
Intranasal instillation of 0.1 mg LPS (E.coli 0111:B4) once a day for 3 consecutive days induced GCM in rat nasal epithelium (as judged by histopathology), with an approx. 50% increase in AB/PAS-stained epithelium compared to untreated controls. A treatment (intraperitoneal (i. p.) injection of 1 or 10 mg/kg) with of the epithelial growth factor receptor (EGFR) inhibitor AG1478 one hour before each LPS administration significantly inhibited LPS-induced GCM (histology assessment) and mucus production. Intranasal instillation of AG1478 one hour after LPS instillation resulted in a similar inhibition of both GCM and mucus production (Takezawa et al., 2016).
Intratracheal instillation of agarose plugs (0.7- to 0.8-mm diameter; 4% agarose type II) in male Fischer 344 rats caused GHC, evidenced by histology and AB/PAS staining. In the airways containing the plugs, goblet cell numbers increased from 0 cells/mm basal lamina to 13.1±5.6, 25.7±15.0, and 51.5±9.0 cells/mm basal lamina after 24, 48, and 72 h, respectively. The percentage of the total length of epithelium staining positively with AB/PAS increased from 0.1 ± 0.1% in control animals to 4.7 ± 1.4, 13.3 ± 0.7, and to 19.1 ± 0.7% at 24, 48, and 72 h, respectively. Muc5ac gene expression was found preferentially in cells that were AB/PAS-positive and increased in a time-dependent manner (Lee et al., 2000).
Analysis of lungs from BALB/c mice sensitized with five i. p. injections of 100 µg ovalbumin (OVA) followed by intranasal instillation of 100 µg OVA, as well as from BALB/c mice treated with 5 µg IL-13 (intranasal instillation on three consecutive days) revealed clear airway GCM 24 h post treatment. Marked MUC5AC mRNA and protein expression (apomucin and glycosylated mucin) were observed in lungs from OVA- and IL-13-treated mice but not in lungs from control saline-treated mice (Alimam et al. 2000).
BALB/c mice were sensitized to OVA with 4 i. p. injections (20 µg each) administered at weekly intervals. They were subsequently exposed for 30 min to an aerosol containing 2.5% OVA. At 3 days post challenge, ca. 60% of the cells in proximal airways were AB-PAS-positive. The number of these cells peaked at day 7 (> 30-fold increase compared with unsensitized controls). The volume density of mucin concomitantly increased on day 3 post challenge with peak measures on day 7 (15-fold increase over baseline) (Evans et al., 2004).
Brown–Norway rats were sensitized by an i. p. injection with 1 mg OVA and 200 mg Al(OH)3 in 1mL of sterile saline on days 0 and 7. The rats were then exposed to aerosolized 1% (w/v) OVA or sterile saline for 30 min on days 14–16. Distinct GCH (evidenced by AB/PAS staining) was observed in the epithelium throughout the airways of the OVA-sensitized and -challenged rats 24 h after the final OVA challenge (on day 17), and the staining progressed to 7-fold increase further on day 24. Marked MUC5AC immunoreactivity was observed in goblet cells similar to the AB/PAS staining pattern. (Takeyama et al., 2008).
Oropharyngeal inspiration of neutrophil elastase (50 µg (43.75 units/40 µl PBS)) by BALB/c mice on day 1, 4, and 7, resulted in GCM as observed on days 8, 11 and 14. The histological mucus index (HMI, defined a grading system of PAS-positive staining, from 0 (no PAS staining) to 4 (>75% of airways epithelium stained) increased from 1 (25% stained area) on day 8 to ca. 2 (26-50%) on day 11, then decreased to 1.3 on day 14, while the HMI remained close to 0 in controls. Muc5ac mRNA expression qualitatively corresponded to AB/PAS histology evolving form 1.64 ± 0,49 on day 8, to 13.53 ± 3.28 on day 11, and 8.62 ± 1.48 on day 14. Muc5ac protein expression followed the same trend (Voynow et al., 2004).
Lungs of C57BL6/J mice treated with house dust mite (HDM) extract (intranasal instillation of 50 µg HDM, 5 days per week for 3 weeks) showed increase in goblet cell number as judged by increased PAS staining in the airway epithelium with concurrent ca. 10-fold increase in Muc5ac expression (Habibovic et al., 2016).
Pyocyanin, a redox-active exotoxin of Pseudomonas aeruginosa, caused increase in goblet cell numbers in mouse airways after 3-week daily intranasal inoculation (25 µg/day). Development of GCM in small terminal bronchioles (88-fold more PAS-stained cells) was paralleled with a 6.4-fold and a 11.4-fold increase in MUC5B-positive cells in large bronchi and terminal bronchioles respectively (Hao et al., 2012).
Male Sprague–Dawley rats that were exposed to 3 ppm acrolein for 6 h a day, for 2 x 5 days separated by a 2-day rest, developed GCM (as judged by histopathology), increasing the % AB/PAS-positive stained epithelium from ca. 5% (in air controls) to 35%. This was accompanied by a nearly 15% increase in Muc5ac-positive stained cells, a ca. 3-fold increase in Muc5ac mRNA expression and a ca. 4-fold increase in protein expression. A treatment with simvastatin, a statin inhibitor of EGFR and extracellular signal-regulated kinase (ERK) activation one day prior exposure to acrolein, significantly inhibited the increase of AB/PAS staining in airway epithelium in a dose-dependent matter. The number of Muc5ac-positive cells was also significantly attenuated, as well as the Muc5ac protein levels in lung homogenates (Chen et al., 2010).
Exposure of female Sprague-Dawley rats to wood smoke (total of 40 g of China fir sawdust smoldered) for 1 h four times per day, five days per week, for three months caused GCM in the airways (as judged by histopathology), a 2-fold increase in Muc5ac gene expression, an increase in the % AB/PAS-positive stained epithelium from approx. 6% (air controls) to ca. 17%, an increase in Muc5ac-positive stained cells from approx. 5% (air controls) to ca. 25% (Huang et al., 2017).
In Sprague-Dawley rats that were whole-body exposed to 4% (v/v air) cigarette smoke (CS) for 1 h daily, for 56 days, the number of goblet cells in the bronchial epithelium significantly increased (ca. 10 cells/mm epithelium in air controls vs 60 cells/mm in CS-treated animals), and the number of Muc5ac-positive cells increased from ca. 20 cells/mm to ca. 80 cells/mm. A treatment with (-)-Epigallocatechin-3-gallate (EGCG, major catechin in green tea, 50 mg/kg oral gavage every other day) significantly reduced the number of goblet cells (PAS-stained) as well as the number of MUC5AC positive cells (Liang et al., 2017).
Bronchial biopsies and epithelial brushings of smokers revealed a significantly larger number of goblet cells compared with healthy control subjects, leading to a 2.2-fold increase in the volume of stored mucin in the epithelium per surface area of basal lamina (4.32 ± 0.55 µm3/µm2 vs 1.94 ± 0.31 µm3/µm2 in controls) (Innes et al., 2006).
The large airways of mice that were whole body exposed to CS of 10 cigarettes (160–180 mg/m3 TPM; TE-10, Teague Enterprises) for 2 h a day, 5 days a week, for up to 12 weeks, exhibited GCH and increased mucus production, evidenced by histology and increases in the numbers of PAS-positive goblet cells (approx. 15% compared to control), Mu5ac mRNA expression (approx. 5-fold increase compared to controls), and Muc5ac-positive cells (approx. 50% compared to control; Zhou et al., 2016).
Ferrets that were exposed to CS (3R4F reference cigarette) for 1 h, twice daily for 6 months developed GCH and GCM in medium and small airways, evidenced by histopathological examination of AB/PAS-stained lung tissues. Mucus expression measured by PAS-positive goblet cell area, normalized by the size of the airway lumen to account for cell variation due to airway diameter, was 60% (0.042% ± 0.025% smoke vs. 0.025% ± 0.013% air control; P = 0.06) higher in smoke-exposed airways than in control airways. Muc5b and Muc5ac staining was greater in smoke-exposed ferrets, but patchy staining made quantification impossible (Raju et al., 2016).
In primary human bronchial epithelial cells differentiated at the air-liquid interface, basolateral treatment with 10 ng/mL IL-13 increased the number of goblet cells from 0.2 ± 0.1 to 15.9 ± 1.1, the number of PAS-positive cells from 2.5 ± 1.5 to 28.2 ± 0.7, and the number of MUC5AC-positive cells from 0.1 ± 0.1 to 25.7 ± 1.0. Reversely, addition of clarithromycin to the IL-13 treatment reduced in a dose dependent manner (maximum with 32 µg/mL) the number of goblet cells from 15.9 ± 1.1 to 4.1 ± 2.5, the number of PAS-positive cells from 28.2 ± 0.7 to 10.7 ± 3.6, and the number of MUC5AC-positive cells from 25.7 ± 1.0 to 5.2 ± 2.9 (Tanabe et al., 2011).
Similarly, a treatment of 3D bronchial organotypic cultures with 5 ng/mL IL-13 for 14 days induced GCH (histopathology assessment). MUC5AC mRNA expression significantly increased (ca. 10-fold) compared with cells treated with DMSO, and MUC5AC protein concentration measured in the supernatant also increased (1.8-fold) compared with DMSO-treated control (Mishina et al., 2015).
In nasal polyp tissues from 8 patients with nasal polyposis, hyperplastic epithelium occupied a mean of 75% (range, 44%-100%). Nasal polyp tissue contained a significantly greater percentage of AB/PAS-and MUC5AC-stained area (approx. 51%) than in control epithelium (approx. 20 %). In nasal polyps, hyperplastic epithelium contained significantly larger numbers of MUC5AC-stained areas (ca. 40%) than in normal pseudostratified epithelium (ca. 15%; Burgel et al., 2000).
Similarly, increase in goblet cell numbers was seen in nasal polyp tissues from 25 patients but not in healthy controls, as evidenced by more PAS-positive epithelial cells (PAS staining index 1.9 [1.3, 2.2] vs 0.7 [0.4, 1.2] in controls). This was accompanied by increased MUC5AC staining, with a mean staining score of 2.2 [1.7, 3.0] in polyp tissues vs 0.6 [0.4, 1.1] in normal controls, and increased MUC5AC gene expression, with levels of 4.4 [2.3, 6.3] in polyp tissues vs 1.2 [0.4, 2.2] in normal controls (Xia et al., 2014).
In patients with COPD, goblet cell increase in lung tissues was confirmed with DAB/PAS staining, a staining specifically targeting mucosubstances such as mucin in cells, (goblet cell rate 0.20 ± 0.10% vs 0.13 ± 0.06% in healthy controls). The rate of MUC5AC expression was also significantly higher in COPD patients (0.27 ± 0.09%) than in healthy control (0.20 ± 0.10%) (Ma et al., 2005).
Healthy smokers had greater goblet cell density (9.80±3.49 cells/mm) than nonsmokers (2.31±1.81 cells/mm) revealed by PAS staining in endobronchial mucosal biopsies. Healthy smokers also had a greater mucin volume density (26.35±10.96 μL/mm2) compared with nonsmokers (5.77±4.34 μL/mm2) (Kim et al., 2015).
Intragastric administration in Sprague-Dawley rats of the thromboxane A2 receptor antagonist seratrodast prior exposure to CS (1h/day, 6 days/week for 4 weeks) significantly attenuated the CS-induced increase in AB/PAS-stained goblets cells and Muc5ac expression in airways (An et al., 2015).
An i. p. treatment of AG1478 (EGFR inhibitor) or/and niflumic acid (calcium activated chloride channels (CLCAs) inhibitor) inhibited CS (6 non-filtered cigarettes/day, 5 days/week, for 2 to 28 days) -induced increase in percentage area of goblet cells (measured by mucin staining) and MUC5AC mRNA expression in rat respiratory epithelium (Hegab et al, 2007)
Airway GCM induced by intratracheal instillation of LPS (200-300 µg) in Sprague-Dawley rats was significantly reduced by daily gavage of a matrix metalloproteinase inhibitor (MMPI, 20 mg/kg) starting 3 days prior of LPS administration and until euthanasia. Area of AB/PAS-stained goblet cells was 3.37 ± 2.36% in control, 71.6 ± 2.56% in LPS and 14.7 ± 4.33% in LPS + MMPI groups. MUC5AC expression was also significantly reduced (6.5-fold) in LPS+MMPI group compared with the LPS group (Kim et al., 2004).
In Sprague-Dawley rats, CS (5 cig twice daily for 4 weeks)- induced increase in goblet cells significantly decreased with i. p. hydrogen-rich saline treatments applied 30 min prior to CS exposure. The AB/PAS-stained area as well as MUC5AC levels were decreased by approx. 50% by hydrogen-rich saline pretreatment (Ning et a., 2013).
CS exposure (5 cig twice daily for 4 weeks) increased goblet cell numbers in mouse airways as shown by an increased area of AB/PAS-staining and Muc5ac-positive staining. Berberine, a strong anti-inflammatory plant alkaloid, administered i. p. every other day (5 and 10 mg/kg) significantly attenuated CS-induced effects on goblets cells and mucin production (Xu et al., 2015).
C57BL/6 wild-type mice exposed to CS (10 cig daily for 4 days) and intranasally inoculated with 50PFU of influenza A/PR8/34 virus showed significantly increased AB/PAS–positive area in the bronchial epithelium. Administration of carbocisteine (mucoregulatory drug) significantly reduced both the AB/PAS-positive areas in bronchial epithelium, and MUC5AC levels in bronchoalveolar lavage (BAL) fluids compared with CS/virus exposed mice (Yageta et al., 2013).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Increase in goblet cell numbers and concomitant increased mucin production developing after exposure to noxious agents, such as allergens, cigarette smoke, pollution, or pathogens has been described in human independently of sex and age. Experimental models exist in mice, rats, guinea pigs, rabbits, dogs, and ferrets.
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An, J., Li, J.-Q., Wang, T., Li, X.-O., Guo, L.-L., et al. (2013). Blocking of thromboxane A2 receptor attenuates airway mucus hyperproduction induced by cigarette smoke. Eur. J. Pharmacol. 703, 11-17.
Atherton, H. C., Jones, G., Danahay, H. (2003). IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L730-L739.
Burgel, P.-R., Escudier, E., Coste, A., Dao-Pick, T., Ueki, I.F., et al. (2000). Relation of epidermal growth factor receptor expression to goblet cell hyperplasia in nasal polyps. J. Allergy Clin. Immunol. 106, 705-712.
Chen, Y.-J., Chen, P., Wang, H.-X., Wang, T., Chen, L., et al. (2010). Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway. Intl. Immunopharmacol. 10, 685-693.
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Hao, Y., Kuang, Z., Xu, Y., Walling, B.E., Lau, G.W. (2013). Pyocyanin-induced mucin production is associated with redox modification of FOXA2. Respir. Res. 14, 82-82.
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Liang, Y., Liu, K.W., Yeung, S.C., Li, X., Ip, M.S. Mak, J.C. (2017). (-)-Epigallocatechin-3-gallate reduces cigarette smoke-induced airway neutrophilic inflammation and mucin hypersecretion in rats. Front. Pharmacol. 8, 618.
Lukacs, N.W., Smit, J.J., Nunez, G., Lindell, D.M. (2010). Respiratory Virus-induced TLR7 activation controls IL-17 associated Increase in mucus via IL-23 regulation: Respiratory virus induced immune environment relies on TLR7-mediated pathways to preserve a non-pathogenic response and regulates IL-17 production. J. Immunol. 185, 2231-2239.
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Takeyama, K., Tamaoki, J., Kondo, M., Isono, K., Nagai, A. (2008). Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen. Clin. Exp. Allergy 38, 857-865.
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