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Event Title

Proliferation of goblet cells, Increase

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

Goblet cells proliferate under normal conditions (Chopra et al., 1981) and in response to a variety of stimulants including virus, bacteria and allergens and EGF (Takeno et al., 1996), (Ichinose et al., 2006), (Camateros et al., 2007), (Shatos et al., 2003), (Duh et al., 2000) in colon, eye, nose and lung. EGFR ligands EGF, HB-EGF and TGFA induce goblet cell proliferation through MAPK, p38 MAPK and JNK in cultured conjunctival goblet cells (Gu et al., 2008), (Shatos et al., 2003).

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?

Methods for measuring proliferation include PCNA staining or immunoblotting, BrdU incorporation, [3H]-thymidine incorporation, and [3H]leucine incorporation. Cell counting MUC5AC+ cells is a non-specific method for assessing proliferation, as increased cell numbers can be due to transdifferentiation.

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. Booth, B.W., Adler, K.B., Bonner, J.C., Tournier, F., and Martin, L.D. (2001). Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-alpha. Am. J. Respir. Cell Mol. Biol. 25, 739–743.

2. Booth, B.W., Sandifer, T., Martin, E.L., and Martin, L.D. (2007). IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17. Respir. Res. 8, 51.

3. 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.

4. Chopra, D.P., Yeh, K., and Brockman, R.W. (1981). Isolation and characterization of epithelial cell types from the normal rat colon. Cancer Res. 41, 168–175.

5. 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.

6. Gu, J., Chen, L., Shatos, M.A., Rios, J.D., Gulati, A., Hodges, R.R., and Dartt, D.A. (2008). Presence of EGF growth factor ligands and their effects on cultured rat conjunctival goblet cell proliferation. Exp. Eye Res. 86, 322–334.

7. 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.

8. 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.

9. Sydlik, U., Bierhals, K., Soufi, M., Abel, J., Schins, R.P.F., and Unfried, K. (2006). Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L725–L733.

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.

11. Tamaoki, J., Isono, K., Takeyama, K., Tagaya, E., Nakata, J., and Nagai, A. (2004). Ultrafine carbon black particles stimulate proliferation of human airway epithelium via EGF receptor-mediated signaling pathway. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L1127–L1133.

12. Taniguchi, K., Yamamoto, S., Aoki, S., Toda, S., Izuhara, K., and Hamasaki, Y. (2011). Epigen is induced during the interleukin-13-stimulated cell proliferation in murine primary airway epithelial cells. Exp. Lung Res. 37, 461–470.