Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|EGFR Activation Leading to Decreased Lung Function||KE||Moderate|
Level of Biological Organization
How this Key Event works
Mucin production in healthy airway provides an important role in trapping and removing bacterial and viral pathogens and particulates. In a disease context such as chronic inflammatory diseases, thickening and overproduction of mucus leads to increased sputum production, narrowing of airways, and difficulty breathing (Voynow and Rubin, 2009).
Various stimuli increase mucin production by goblet cells including cigarette smoke or other oxidants (Shao et al., 2004), (Takeyama et al., 2001), (Yu et al., 2011), (Casalino-Matsuda et al., 2009), including phorbol 12-myristate 13-acetate (PMA), 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and sulfur dioxide (Hewson et al., 2004), (Lee et al., 2011), (Lamb and Reid, 1968) as well as bacteria (Dohrman et al., 1998), (Hao et al., 2014). These stimuli act through the EGFR pathway to induce mucus production, shown by decreased mucus production in response to EGFR inhibition (Nadel, 2013).
MUC5AC is the main mucin gene upregulated and secreted in airway inflammation and COPD. MUC5B is also found predominantly in small airways of COPD patients, and MUC2 makes up 2% of COPD sputum mucin. (Williams et al., 2006). MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7, MUC8, MUC11, MUC13, MUC15, MUC19, and MUC2 are expressed in the airway, with MUC1 and MUC4 at the apical surface of ciliated cells, MUC5AC, MUC5B and MUC2 expressed in and secreted by goblet cells, MUC5B expressed in mucous cells of the submucosal gland, and MUC7 expressed in serous cells of submucosal gland (Voynow and Rubin, 2009). MUC2 and MUC5AC have been associated with EGFR expression in rats and mice (Leikauf et al., 2002).
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
MUC5AC promoter activity is measured by luciferase activity.
MUC5AC RNA is measured by RT-PCR.
MUC5AC protein is measured by immunofluorescence, immunoblotting, ELISA and quantitative slot blot analysis.
Mucin production is measured by AB-PAS staining and enzyme-linked lectin assay (ELLA) is used to evaluate total mucin protein release.
Evidence Supporting Taxonomic Applicability
Mucus production has been well-documented in mouse, human and rat. Within these species, mucin genes are orthologous including MUC5AC, MUC5B, MUC2, MUC6, MUC13, MUC15, MUC16, MUC19, MUC20.
1. Casalino-Matsuda, S., Monzon, M., Day, A., and Forteza, R. (2009). Hyaluronan fragments/CD44 mediate oxidative stress-induced MUC5B up-regulation in airway epithelium. Am J Respir Cell Mol Biol 40, 277–285.
2. Dohrman, A., Miyata, S., Gallup, M., Li, J.D., Chapelin, C., Coste, A., Escudier, E., Nadel, J., and Basbaum, C. (1998). Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria. Biochim. Biophys. Acta 1406, 251–259.
3. 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.
4. Hewson, C., Edbrooke, M., and Johnston, S. (2004). PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol 344, 683–695.
5. Lamb, D., and Reid, L. (1968). Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchial epithelium during exposure to sulphur dioxide. J. Pathol. Bacteriol. 96, 97–111.
6. Lee, Y.C., Oslund, K.L., Thai, P., Velichko, S., Fujisawa, T., Duong, T., Denison, M.S., and Wu, R. (2011). 2,3,7,8-Tetrachlorodibenzo-p-dioxin–Induced MUC5AC Expression. Am. J. Respir. Cell Mol. Biol. 45, 270–276.
7. Leikauf, G.D., Borchers, M.T., Prows, D.R., and Simpson, L.G. (2002). Mucin apoprotein expression in COPD. Chest 121, 166S – 182S.
8. Shao, M., Nakanaga, T., and Nadel, J. (2004). Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. Am J Physiol Lung Cell Mol Physiol 287, L420–L427.
9. 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.
10. Voynow, J., and Rubin, B. (2009). Mucins, mucus, and sputum. Chest 135, 505–512.
11. Williams, O., Sharafkhaneh, A., Kim, V., Dickey, B., and Evans, C. (2006). Airway mucus: From production to secretion. Am J Respir Cell Mol Biol 34, 527–536.
12. Yu, H., Li, Q., Zhou, X., Kolosov, V., and Perelman, J. (2011). Role of hyaluronan and CD44 in reactive oxygen species-induced mucus hypersecretion. Mol Cell Biochem 352, 65–75.