Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Decreased lung function||KeyEvent|
Key Event Description
Metaplasia is the replacement of a differentiated cell type with another differentiated cell type. In the case of goblet cell metaplasia, ciliated or club 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. This adaptive change in the airway epithelium is often observed following exposure to respiratory irritants including ozone, endotoxin and cigarette smoke (Harkema & Hotchkiss, 1993; Harkema & Wagner, 2002; Mebratu et al., 2011).
How It Is Measured or Detected
In vitro and in vivo studies assess metaplasia by looking for co-expression of cell markers or characteristics of two cell types though to be goblet cell progenitors, i.e. the club cell and the ciliated cell. CC-10/CSSP is commonly used as a club cell marker (Reader et al., 2003; Hayashi et al., 2004; Evans et al., 2004), while FOXJ1, beta-tubulin, tektin and DNAH9 were 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 glutamylated tubulins are other characteristics of ciliated cells (Laoukili et al., 2001). Transdifferentiation and metaplasia are said to occur when these ciliated cell characteristics and markers decrease, while expression of goblet cell markers such as MUC5AC and other mucin proteins increases. Light 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).
In clinical samples, a pathologist may determine absence/presence of metaplasia. This assessment is not standardized, but based on experience, and may be semiquantitative if a score is assigned in relation to the extent of the finding.
Domain of Applicability
Goblet cell metaplasia from ciliated cells has been observed in human (Gomperts et al. 2007; Laoukili et al., 2001; Yoshisue and Hasegawa, 2004; Turner et al., 2011; Casalino-Matsuda et al., 2006) and in mouse (Fujisawa et al., 2008; Tyner et al., 2006). Studies in rat have not directly measured transdifferentiation of ciliated to goblet cells. However, airway remodeling of epithelium with nearly no goblet cells to an epithelium with numerous goblet cells was observed (Harkema and Hotchkiss, 1993).
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.
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.
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 13, 191–202.
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.
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.
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.
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.
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.
Lumsden, A.B., McLean, A., and Lamb, D. (1984). Goblet and Clara cells of human distal airways: evidence for smoking induced changes in their numbers. Thorax 39, 844-849.
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.
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.
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.
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.
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.
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.