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Event Title

Hyperplasia of goblet cells

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

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Strong NCBI
mouse Mus musculus Strong NCBI
rat Rattus norvegicus Strong NCBI

Level of Biological Organization

Biological Organization

How this Key Event works

Hyperplasia is increased cell production in a normal tissue or organ. Goblet cell hyperplasia arises from a variety of stimulants inducing goblet cell proliferation including virus, bacteria, (Takeno et al., 1996), cigarette smoke (Carter et al., 2012), (Mebratu et al., 2011), allergens (Ichinose et al., 2006), (Camateros et al., 2007) and EGF (Shatos et al., 2003), (Duh et al., 2000) in colon, eye, nose and lung.

Goblet cell hyperplasia occurs in smokers with chronic bronchitis (Saetta et al., 2000) and COPD patients (Ma et al., 2005), which can lead to declined lung function due to hypersecretion of mucus and airflow obstruction (Caramori et al., 2009).

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?

In vitro/in vivo

Hyperplasia is measured by an increase in goblet cell proliferation, including PCNA immunofluorescence or immunoblotting, BrdU incorporation, [3H]-thymidine incorporation, and [3H]leucine incorporation.

Hyperplasia is sometimes non-specifically measured by an increase in number of MUC5AC+ cells by immunofluorescence, increase in MUC5AC protein by immunoblotting or ELISA or an increase in mucin production by AB-PAS staining. These studies do not consider the origin for the increase in goblet cells, whether it be from proliferating goblet cells or cells that are transdifferentiating into goblet cells.


Hyperplasia is measured by a pathologist as an increase in the number of goblet cells in an epithelium which normally contains some goblet cells (Harkema and Hotchkiss, 1993).

Evidence Supporting Taxonomic Applicability

Goblet cells have been reported to proliferate in human, mouse and rat studies (Takeno et al., 1996), (Ichinose et al., 2006), (Camateros et al., 2007), (Shatos et al., 2003), (Duh et al., 2000).


1. Camateros, P., Tamaoka, M., Hassan, M., Marino, R., Moisan, J., Marion, D., Guiot, M.-C., Martin, J.G., and Radzioch, D. (2007). Chronic asthma-induced airway remodeling is prevented by toll-like receptor-7/8 ligand S28463. Am. J. Respir. Crit. Care Med. 175, 1241–1249.

2. Caramori, G., Casolari, P., Di Gregorio, C., Saetta, M., Baraldo, S., Boschetto, P., Ito, K., Fabbri, L., Barnes, P., Adcock, I., et al. (2009). MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathology 55, 321–331.

3. Carter, C., Misra, M., and Maronpot, R. (2012). Tracheal Morphologic and Protein Alterations FollowingShort-Term Cigarette Mainstream Smoke Exposure to Rats. J Toxicol Pathol 25, 201–207.

4. Duh, G., Mouri, N., Warburton, D., and Thomas, D.W. (2000). EGF regulates early embryonic mouse gut development in chemically defined organ culture. Pediatr. Res. 48, 794–802.

5. Ichinose, T., Sadakane, K., Takano, H., Yanagisawa, R., Nishikawa, M., Mori, I., Kawazato, H., Yasuda, A., Hiyoshi, K., and Shibamoto, T. (2006). Enhancement of mite allergen-induced eosinophil infiltration in the murine airway and local cytokine/chemokine expression by Asian sand dust. J. Toxicol. Environ. Health A 69, 1571–1585.

6. 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.

7. Mebratu, Y., Schwalm, K., Smith, K., Schuyler, M., and Tesfaigzi, Y. (2011). Cigarette smoke suppresses Bik to cause epithelial cell hyperplasia and mucous cell metaplasia. Am J Respir Crit Care Med 183, 1531–1538.

8. Saetta, M., Turato, G., Baraldo, S., Zanin, A., Braccioni, F., Mapp, C., Maestrelli, P., Cavallesco, G., Papi, A., and Fabbri, L. (2000). Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 161, 1016–1021.

9. Shatos, M.A., Ríos, J.D., Horikawa, Y., Hodges, R.R., Chang, E.L., Bernardino, C.R., Rubin, P.A.D., and Dartt, D.A. (2003). Isolation and characterization of cultured human conjunctival goblet cells. Invest. Ophthalmol. Vis. Sci. 44, 2477–2486.

10. Takeno, S., Hamamura, N., Tatsukawa, T., and Yazin, K. (1996). [Proliferating cell nuclear antigen (PCNA) immunolocalization in human nasal epithelium with chronic sinusitis detected by confocal laser scanning microscopy]. Nihon Jibiinkoka Gakkai Kaiho 99, 1119–1125.