Upstream eventGoblet cell hyperplasia
Increase, Mucin production
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|EGFR Activation Leading to Decreased Lung Function||adjacent||Moderate||Low|
Life Stage Applicability
Key Event Relationship Description
This KER is inferred based on the notion that "Secretory cell hyperplasia is a prerequisite for sustained mucus hypersecretion/mucin overproduction" (Rose and Voynow, 2006).
Goblet cell hyperplasia refers to the increase in goblet cell numbers and is as common feature of airway epithelia in asthma and other respiratory diseases. It can arise from sustained proliferation of this cell population following airway injury by, for example, exposure to allergens, pathogens, cigarette smoke and other inhalation exposures (Miyabara et al., 1998; Nagao et al., 2003; Saetta et al., 2000; van Hove et al., 2009; Walter et al., 2002; Hao et al., 2014; Lukacs et al., 2010; Hao et al., 2013; Yageta et al., 2014; Nie et al., 2012; Hegab et al., 2007; Kim et al., 2016). Since goblet cells are mucin-producing cells, an increase in goblet cell numbers would consequently equate to an increase (from basal levels) in mucin production.
Evidence Supporting this KER
This KER is inferred. However, there is indirect evidence demonstrating an increase in mucin production, which is frequently equated with increased MUC5AC mRNA and protein expression, in the presence of goblet cell hyperplasia as judged by an increase in Alcian Blue/periodic acid Schiff and/or MUC5AC-positive staining in airway epithelia following inhalation exposures (Casalino-Matsuda et al., 2006; Takeyama et al., 2001).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Casalino-Matsuda, S.M., Monzón, M.E., and 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 Resp Cell Mol Biol 34, 581-591.
Hao, Y., Kuang, Z., Jing, J., Miao, J., Mei, L.Y., Lee, R.J., Kim, S., Choe, S., Krause, D.C., and Lau, G.W. (2014). Mycoplasma pneumoniae Modulates STAT3-STAT6/EGFR-FOXA2 Signaling To Induce Overexpression of Airway Mucins. Infect Immun 82, 5246–5255.
Hao, Y., Kuang, Z., Xu, Y., Walling, B.E., and Lau, G.W. (2013). Pyocyanin-induced mucin production is associated with redox modification of FOXA2. Resp Res 14, 82-82.
Hegab, A.E., Sakamoto, T., Nomura, A., Ishii, Y., Morishima, Y., Iizuka, T., Kiwamoto, T., Matsuno, Y., Homma, S., and Sekizawa, K. (2007). Niflumic acid and AG-1478 reduce cigarette smoke-induced mucin synthesis: The role of hCLCA1. Chest 131, 1149-1156.
Kim, B.-G., Lee, P.-H., Lee, S.-H., Kim, Y.-E., Shin, M.-Y., Kang, Y., Bae, S.-H., Kim, M.-J., Rhim, T., Park, C.-S., et al. (2016). Long-Term Effects of Diesel Exhaust Particles on Airway Inflammation and Remodeling in a Mouse Model. Allergy Asthma Immunol Res 8, 246-256.
Lukacs, N.W., Smit, J.J., Nunez, G., and 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.
Miyabara, Y., Ichinose, T., Takano, H., Lim, H. B., & Sagai, M. (1998). Effects of diesel exhaust on allergic airway inflammation in mice. J Allergy Clin Immunol 102, 805-812.
Nagao, K., Tanaka, H., Komai, M., Masuda, T., Narumiya, S., and Nagai, H. (2003). Role of Prostaglandin I2 in Airway Remodeling Induced by Repeated Allergen Challenge in Mice. Am J Resp Cell Mol Biol 29, 314-320.
Nie, Y.-C., Wu, H., Li, P.-B., Luo, Y.-L., Zhang, C.-C., Shen, J.-G., and Su, W.-W. (2012). Characteristic comparison of three rat models induced by cigarette smoke or combined with LPS: to establish a suitable model for study of airway mucus hypersecretion in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 25, 349-356.
Rose, M.C., and Voynow, J.A. (2006). Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 86, 245-278.
Saetta, M., Turato, G., Baraldo, S., Zanin, A., Braccioni, F., Mapp, C.E., Maestrelli, P., Cavallesco, G., Papi, A., and Fabri, L.M. (2000). Goblet Cell Hyperplasia and Epithelial Inflammation in Peripheral Airways of Smokers with Both Symptoms of Chronic Bronchitis and Chronic Airflow Limitation.Am J Resp Crit Care Med 161, 1016-1021.
Takeyama, K., Jung, B., Shim, J., Burgerl, P., Dao-Pick, T., Ueki, I., Protin, U., Kroschel, P., and Nadel, J. (2001). Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am J Physiol Lung Cell Mol Physiol 280, L165–L172.
Van Hove, C. L., Maes, T., Cataldo, D. D., Guéders, M. M., Palmans, E., Joos, G. F., & Tournoy, K. G. (2009). Comparison of acute inflammatory and chronic structural asthma-like responses between C57BL/6 and BALB/c mice. Int Arch Allergy Immunol 149, 195-207.
Walter, M.J., Morton, J.D., Kajiwara, N., Agapov, E., and Holtzman, M.J. (2002). Viral induction of a chronic asthma phenotype and genetic segregation from the acute response. J Clin Invest 110, 165-175.
Yageta, Y., Ishii, Y., Morishima, Y., Ano, S., Ohtsuka, S., Matsuyama, M., Takeuchi, K., Itoh, K., Yamamoto, M., and Hizawa, N. (2014). Carbocisteine reduces virus-induced pulmonary inflammation in mice exposed to cigarette smoke. Am J Resp Cell Mol Biol 50, 963-973.