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
Metaplasia is the replacement of a differentiated cell type with another differentiated cell type. In the case of goblet cell metaplasia, ciliated or Clara cells transdifferentiate into goblet cells (Tyner et al., 2006), (Evans et al., 2004), leading to an increased number of mucus-producing cells and eventually mucus hypersecretion. There is an inverse relationship between goblet cell metaplasia and FEV1, a measure of lung function (Nagai et al., 1995).
Ozone and endotoxin induce mucus cell metaplasia (Harkema and Hotchkiss, 1993), (Harkema and Wagner, 2002), along with cigarette smoke (Mebratu et al., 2011). These stimulants can activate EGFR which leads to downstream signaling that increases goblet cells and mucus production.
Metaplasia may be more dominant than hyperplasia in response to endotoxin and sulfur dioxide, as studies have found low mitotic rates along with increased number of goblet cells, suggesting differentiation into goblet cells is occurring (Shimizu et al., 1996), (Lamb and Reid, 1968).
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 experiments
Studies measure metaplasia by looking for co-expression of cell markers or characteristics of two cell types: the progenitor cell that is differentiating into the goblet cell. Both Clara and ciliated cells have been studied as goblet cell progenitors: CSSP is used as a Clara cell marker (Reader et al., 2003), (Hayashi et al., 2004), (Evans et al., 2004), while FOXJ1, beta-tubulin, tektin and DNAH9 are used as ciliated markers (Yoshisue and Hasegawa, 2004), (Gomperts et al. 2007), (Turner et al., 2011), (Fujisawa et al., 2008). Apical localization of ezrin, ciliary beat frequency and glutamuylated tubulins are other characteristics of ciliated cells (Laoukili et al., 2001). Transdifferentiation and metaplasia are said to occur when these Clara cell and ciliated cell characteristics and markers decrease while goblet cell markers increase, MUC5AC and other mucin proteins. Electron or fluorescence microscopy is used to show co-expression of markers and a transitory cell type (observation of goblet and cilia cell features within the same cell) (Tyner et al., 2006), (Laoukili et al., 2001), (Gomperts et al., 2007).
Metaplasia is assessed by a pathologist by the replacement of cells that are not normally at that location.
Evidence Supporting Taxonomic Applicability
Goblet cell metaplasia from ciliated cells has been observed extensively in human (Gomperts et al. 2007), (Laoukili et al., 2001), (Yoshisue and Hasegawa, 2004), (Turner et al., 2011), (Casalino-Matsuda et al., 2006) and moderately in mouse (Fujisawa et al., 2008), (Tyner et al., 2006). Studies in rat have not directly measured transdifferentiation of ciliated to goblet cells, however detected transformation of epithelium with no mucous cells into an epithelium with numerous mucus cells (Harkema and Hotchkiss, 1993).
1. Casalino-Matsuda, S., Monzón, M., and Forteza, R. (2006). Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium. Am J Respir Cell Mol Biol 34, 581–591.
2. Evans, C.M., Williams, O.W., Tuvim, M.J., Nigam, R., Mixides, G.P., Blackburn, M.R., DeMayo, F.J., Burns, A.R., Smith, C., Reynolds, S.D., et al. (2004). Mucin is produced by clara cells in the proximal airways of antigen-challenged mice. Am. J. Respir. Cell Mol. Biol. 31, 382–394.
3. Fujisawa, T., Ide, K., Holtzman, M.J., Suda, T., Suzuki, K., Kuroishi, S., Chida, K., and Nakamura, H. (2008). Involvement of the p38 MAPK pathway in IL-13-induced mucous cell metaplasia in mouse tracheal epithelial cells. Respirol. Carlton Vic 13, 191–202.
4. Harkema, J., and Hotchkiss, J. (1993). Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: novel animal models to study toxicant-induced epithelial transformation in airways. Toxicol Lett 68, 251–263.
5. Harkema, J., and Wagner, J. (2002). Non-allergic models of mucous cell metaplasia and mucus hypersecretion in rat nasal and pulmonary airways. Novartis Found Symp 248, 181–197; discussion 197–200, 277–282.
6. Hayashi, T., Ishii, A., Nakai, S., and Hasegawa, K. (2004). Ultrastructure of goblet-cell metaplasia from Clara cell in the allergic asthmatic airway inflammation in a mouse model of asthma in vivo. Virchows Arch. Int. J. Pathol. 444, 66–73.
7 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.
8. Laoukili, J., Perret, E., Willems, T., Minty, A., Parthoens, E., Houcine, O., Coste, A., Jorissen, M., Marano, F., Caput, D., et al. (2001). IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J. Clin. Invest. 108, 1817–1824.
9. Nagai, A., Thurlbeck, W.M., and Konno, K. (1995). Responsiveness and variability of airflow obstruction in chronic obstructive pulmonary disease. Clinicopathologic correlative studies. Am. J. Respir. Crit. Care Med. 151, 635–639.
10. Reader, J.R., Tepper, J.S., Schelegle, E.S., Aldrich, M.C., Putney, L.F., Pfeiffer, J.W., and Hyde, D.M. (2003). Pathogenesis of mucous cell metaplasia in a murine asthma model. Am. J. Pathol. 162, 2069–2078.
11. Shimizu, T., Takahashi, Y., Kawaguchi, S., and Sakakura, Y. (1996). Hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium induced by endotoxin. Am. J. Respir. Crit. Care Med. 153, 1412–1418.
12. Turner, J., Roger, J., Fitau, J., Combe, D., Giddings, J., Heeke, G.V., and Jones, C.E. (2011). Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway epithelium. Am. J. Respir. Cell Mol. Biol. 44, 276–284.
13. Tyner, J., Tyner, E., Ide, K., Pelletier, M., Roswit, W., Morton, J., Battaile, J., Patel, A., Patterson, G., Castro, M., et al. (2006). Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. J Clin Invest 116, 309–321.
14. Yoshisue, H., and Hasegawa, K. (2004). Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells. Biosci Biotechnol Biochem 68, 2024–2031.