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Increase, Mucin production leads to Chronic, Mucus hypersecretion
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 Do not cite||Under Development|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
Key Event Relationship Description
Chronic mucus hypersecretion, i.e., the sustained production of mucus, is a main feature of chronic lung diseases. The presence of goblet cell hyperplasia or goblet cell metaplasia in the lungs of chronic obstructive pulmonary disease, asthma and cystic fibrosis patients has been inferred as cause for sustained mucus production, because the increased number (or increased size) of goblet cells is associated with an increase in the volume of mucus produced (Jackson, 2001; Innes et a. 2006; Rose and Voynow, 2006; Munkholm and Mortensen, 2014).
Evidence Collection Strategy
Evidence Supporting this KER
Mucus hypersecretion is a feature of animal models of asthma (Shim et al., 2001; Singer et al., 2004; Song et al., 2016) and occurs in mice and rats following inhalation of e.g. acrolein and cigarette smoke (Deshmukh et al., 2008; Yang et al., 2012; Chen et al., 2013; Vlahos and Bozinovski, 2014; Liu et al., 2017). There appears to be no consensus as to the "chronicity" of mucus hypersecretion, and because there are no standardized measures of mucus hypersecretion, experimental evidence is limited. Clinically, (chronic) mucus hypersecretion is defined as coughing and sputum production for >3 months in at least two consecutive years and called "chronic bronchitis" (Vestbo, 2002). Long-term smokers with and without airflow obstruction present with chronic mucus hypersecretion and increased mucin production (O'Donnell et al., 2004; Caramori et al., 2004; Innes et al., 2006; Kim et al., 2008).
Chronic mucus hypersecretion, i.e., the sustained production of mucus, is the key symptom of COPD and asthma, and is also observed in patients with bronchiectasis and cystic fibrosis. To a certain extent, it can also be modeled in animals as has been shown in mouse models of asthma. We therefore consider this KER to be biologically plausible with moderate confidence.
Uncertainties and Inconsistencies
Caramori et al. (2009) found no correlation between MUC5AC immunostaining and the presence of chronic bronchitis. Kim et al. (2015) reported higher goblet cell numbers and mucin volume density in healthy smokers than in COPD patients and also no difference in mucin volume density between smokers with and without chronic bronchitis.
In some instances, sputum or phlegm production/output may have been considered quantitative evidence for chronic mucus hypersecretion. However, Danahay and Jackson (2005) noted that "[sputum] represents an indirect measure of the contribution that mucus makes to that part of the airway secretions that is amenable to clearance. It is possible that the bulk of the disease modifying potential of the mucus-hypersecretory phenotype does not directly relate to cleared mucus/sputum..."
Known modulating factors
There was a marked increase in MUC5AC immunostaining in the bronchial epithelium of smokers compared to nonsmokers, and there was a significant correlation between % MUC5AC-stained epithelial area and the numbers of epithelial cells staining positively for both MUC5AC and PAS (O'Donnell et al., 2004).
In the bronchiolar epithelium, intraluminal AB/PAS staining was significantly more frequent among COPD subjects than smokers or never-smokers (1 ⁄ 6, 2 ⁄ 11 and 7 ⁄ 9 in never-smokers, smokers and COPD subjects). MUC5AC expression was also significantly higher in COPD subjects compared with smokers and never-smokers (score [0 indicating absence of staining, 1 indicating a staining limited to cilia, 2 indicating supranuclear cytoplasmic staining, 3 indicating supranuclear cytoplasmic staining and staining of goblet cells]: 2 (1–2.3) in COPD vs 0 (0–1) in never-smokers and 0.5 (0–1) in smokers) (Caramori et al., 2009).
In a small study of 24 cigarette smokers and 19 non-smoking control subjects, the goblet cell number per surface area of basal lamina in the large airways was 80% higher in smokers (56,232 + 5611 vs 41,996 + 4610), with a 30% higher mean volume of individual goblet cells ( 2,925 + 173 µm3 vs 2,259 + 192 µm3) than in non-smokers. MUC5AC immunostaining in the surface airway epithelium was also 80% higher in smokers than in control subjects (volume of epithelial MUC5AC per surface area of basal lamina: 6.82 + 0.98 µm3/µm2 vs 3.70 + 0.69 µm3/µm2) (Innes et al., 2006).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Mucus hypersecretion occurs in mice and rats (Shim et al., 2001; Singer et al., 2004; Song et al., 2016; Deshmukh et al., 2008; Yang et al., 2012; Chen et al., 2013; Vlahos and Bozinovski, 2014; Liu et al., 2017) and in humans (Vestbo, 2002; O'Donnell et al., 2004; Caramori et al., 2004; Innes et al., 2006; Kim et al., 2008).
Caramori, G., Casolari, P., Di Gregorio, C., Saetta, M., Baraldo, S., Boschetto, P., et al. (2009). MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathology 55, 321-331.
Chen, P., Deng, Z., Wang, T., Chen, L., Li, J., Feng, Y., et al. (2013). The potential interaction of MARCKS-related peptide and diltiazem on acrolin-induced airway mucus hypersecretion in rats. Int. Immunopharmacol. 17, 625-632.
Danahay, H., and Jackson, A.D. (2005). Epithelial mucus-hypersecretion and respiratory disease. Curr. Drug Targets Inflamm. Allergy 4, 651-664.
Deshmukh, H.S., Shaver, C., Case, L.M., Dietsch, M., Wesselkamper, S.C., Hardie, W.D., et al. (2008). Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am. J. Respir. Cell Mol. Biol. 38, 446-454.
Jackson, A.D. (2001). Airway goblet-cell mucus secretion. Trends Pharmacol. Sci. 22, 39-45.
Kim, V., Kelemen, S.E., Abuel-Haija, M., Gaughan, J.P., Sharafkaneh, A., Evans, C.M., et al. (2008). Small airway mucous metaplasia and inflammation in chronic obstructive pulmonary disease. COPD 5, 329-338.
Kim, V., Oros, M., Durra, H., Kelsen, S., Aksoy, M., Cornwell, W.D., et al. (2015). Chronic Bronchitis and Current Smoking Are Associated with More Goblet Cells in Moderate to Severe COPD and Smokers without Airflow Obstruction. PLoS ONE 10, e0116108.
Liu, Z., Geng, W., Jiang, C., Zhao, S., Liu, Y., Zhang, Y., et al. (2017). Hydrogen-rich saline inhibits tobacco smoke-induced chronic obstructive pulmonary disease by alleviating airway inflammation and mucus hypersecretion in rats. Exp. Biol. Med. 242, 1534-1541.
Munkholm, M., and Mortensen, J. (2014). Mucociliary clearance: pathophysiological aspects. Clin. Physiol. Funct. Imaging 34, 171-177.
O’Donnell, R., Richter, A., Ward, J., Angco, G., Mehta, A., Rousseau, K., et al. (2004). Expression of ErbB receptors and mucins in the airways of long term current smokers. Thorax 59, 1032-1040.
Rose, M.C., and Voynow, J.A. (2006). Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol. Rev. 86, 245-278.
Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., et al. (2001). IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L134-140.
Singer, M., Martin, L.D., Vargaftig, B.B., Park, J., Gruber, A.D., Li, Y., et al. (2004). A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nat. Med. 10, 193-196.
Song, L., Tang, H., Liu, D., Song, J., Wu, Y., Qu, S., et al. (2016). The chronic and short-term effects of gefinitib on airway remodeling and inflammation in a mouse model of asthma. Cell. Physiol. Biochem. 38, 194-206.
Vestbo, J. (2002). Epidemiological studies in mucus hypersecretion. Novartis Found. Symp. 248, 3-12; discussion: 12-19, 277-282.
Vlahos, R., and Bozinovski, S. (2014). Recent advances in pre-clinical mouse models of COPD. Clin. Sci. 126, 253-265.
Yang, T., Luo, F., Shen, Y., An, J., Li, X., Liu, X., et al. (2012). Quercetin attenuates airway inflammation and mucus production induced by cigarette smoke in rats. Int. Immunopharmacol. 13, 73-81.