Upstream eventChronic, Mucus hypersecretion
Decrease, Lung function
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|EGFR Activation Leading to Decreased Lung Function||adjacent||High||Moderate|
Life Stage Applicability
Key Event Relationship Description
Increased mucin production and mucus hypersecretion following acute exposure are thought to contribute to innate airway defenses and are most likely limited by anti-inflammatory mechanisms aimed at resolving the exposure-related stress (Rose and Voynow 2006; Ramos et al., 2014]. However, under chronic exposure conditions, airway remodeling will persist, leading to airway narrowing, and the elevated number of goblet cells results in higher basal mucus levels (Rogers, 2007). Eventually, increased mucin production and mucus hypersecretion may lead to airway obstruction and a progressive decline in lung function over time (Kim and Criner, 2015; Aoshiba and Nagai, 2004; Vestbo et al, 1996).
Evidence Supporting this KER
Clinical studies showed that MUC5AC expression in bronchial epithelium was inversely correlated with FEV1 (% predicted) and with FEV1/FVC ratio (Caramori et al., 2009; Innes et al., 2006), and epidemiological evidence indicates a link between mucus hypersecretion and decreased lung function (Allinson et al., 2015; Pistelli et al., 2003; Vestbo et al., 1996). As a cause-effect relationship between goblet cell hyperplasia/metaplasia, increased mucin production, mucus hypersecretion and airway obstruction cannot be conclusively proven, these findings support moderate biological plausibility.
Goblet cell hyperplasia and MUC5AC expression, both of which contribute to mucus hypersecretion, were increased in the airways of COPD patients compared with non-COPD patients (with normal lung function) (Ma et al., 2005). The volume of epithelial mucin stores was larger in bronchial biopsies from smokers with than in those without airflow obstruction and correlated with the FEV1/FVC ratio (Innes et al., 2006). Another study showed that MUC5AC expression in bronchial epithelium was inversely correlated with FEV1 (% predicted) (Caramori et al., 2009). Epidemiological data indicated that self-reported symptoms including chronic sputum production and/or chronic cough in middle-aged current smokers increased the likelihood of airflow limitation at later stages of life and that lung function declines more rapidly the longer chronic mucus hypersecretion persists, at least in this middle-age group (Vestbo et al., 1996; Allinson et al., 2015; Pistelli et al., 2003).
Uncertainties and Inconsistencies
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 goblet cell hyperplasia, 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.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Allinson, J.P., Hardy, R., Donaldson, G.C., Shaheen, S.O., Kuh, D., and Wedzicha, J.A. (2016). The presence of chronic mucus hypersecretion across adult life in relation to chronic obstructive pulmonary disease development. Am J Resp Crit Care Med 193, 662-672.
Aoshiba, K., and Nagai, A. (2004). Differences in airway remodeling between asthma and chronic obstructive pulmonary disease. Clin Rev Allergy Immunol 27, 35-43.
Caramori, G., Casolari, P., Di Gregorio, C., Saetta, M., Baraldo, S., Boschetto, P., Ito, K., Fabbri, L.M., Barnes, P.J., and Adcock, I.M. (2009). MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathology 55, 321-331.
Innes, A.L., Woodruff, P.G., Ferrando, R.E., Donnelly, S., Dolganov, G.M., Lazarus, S.C., and Fahy, J.V. (2006). Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 130, 1102-1108.
Kim, V., and Criner, G.J. (2015). The chronic bronchitis phenotype in chronic obstructive pulmonary disease: features and implications. Curr Opin Pulm Med 21, 133-141.
Ma, R., Wang, Y., Cheng, G., Zhang, H., Wan, H., and Huang, S. (2005). MUC5AC expression up-regulation goblet cell hyperplasia in the airway of patients with chronic obstructive pulmonary disease. Chin Med Sci J 20, 181-184.
Pistelli, R., Lange, P., and Miller, D.L. (2003). Determinants of prognosis of COPD in the elderly: mucus hypersecretion, infections, cardiovascular comorbidity. Eur Resp J 21, 10s-14s.
Rogers, D.F. (2007). Physiology of airway mucus secretion and pathophysiology of hypersecretion. Resp Care 52, 1134-1149.
Rose, M.C., and Voynow, J.A. (2006). Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 86, 245-278.
Vestbo, J., Prescott, E., and Lange, P. (1996). Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Resp Crit Care Med 153, 1530-1535.