Key Event Title
|Level of Biological Organization|
Key Event Components
|transdifferentiation||ciliated epithelial cell||occurrence|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Decreased lung function||KeyEvent|
Key Event Description
Transdifferentiation of ciliated epithelial cells into goblet cells results in goblet cell metaplasia and, as a consequence, mucus hypersecretion.
Airway epithelial injury can be caused by various inhalation exposures (e.g. cigarette smoke, sulphur dioxide, endotoxin, viruses). Subsequent tissue repair processes are thought to initiate the transdifferentiation process, whereby ciliated epithelial cells first dedifferentiate and then redifferentiate to goblet cells, without an apparent increase in the total number of epithelial cells (Lumsden et al., 1984; Shimizu et al., 1996; Reader et al., 2003).
Alternatively, transdifferentiation may occur following the activation of EGFR-mediated anti-apoptotic signaling in ciliated epithelial cells. Subsequent stimulation by proinflammatory stimuli such as the Th2 cytokines interleukin (IL)-4 and IL-13 then promotes transdifferentiation of ciliated cells into goblet cells, thereby increasing the number of goblet cells (“second hit hypothesis”) in mouse tracheal epithelium and airway epithelia of COPD patients (Laoukili et al., 2001; Tyner et al., 2006; Curran & Cohn, 2010).
Current knowledge pertaining to how inhibition of ciliated cell apoptosis leads to transdifferentiation that eventually contributes to an increase in goblet cell numbers is still incomplete. The available evidence for this KE is indirect or correlative (Tyner et al., 2006; Silva et al., 2012; Reader et al., 2003; Turner et al., 2011; Ayers et al., 1988; Jefferey et al., 1984). It also is not in agreement with other studies, which show that ciliated cells do not give rise to goblet cells during airway remodeling in rodents and humans, and with studies that provide evidence for increased goblet cell proliferation (Lumsden et al., 1984; Casalino-Matsuda et al., 2006; Hays et al., 2006; Tesfaigzi et al., 2004; Taniguchi et al., 2011).
How It Is Measured or Detected
Ciliated epithelial cells are characterized by cilia beating, apical localization of ezrin and basal bodies, and expression of Foxj1 and glutamylated tubulin (Laoukili et al., 2001; Gomperts et al., 2007). Ciliated epithelial cells may be detected by light or electron microscopy, although the latter is typically used for ultrastructural evaluation rather than enumeration of this cell type. Instead, immunocytochemical labelling with anti-tubulin or anti-Foxj1 antibodies is frequently employed to establish ciliated epithelial cell count on histological sections of tissues; flow cytometric analysis also appears to be used rather infrequently for this purpose.
Goblet cells are mucin-producing columnar epithelial cells, and their secretory granules can be identified easily by light or electron microscopy (Rogers, 1994). However, MUC5AC immunohistochemical staining is typically used to identify and enumerate this cell type in tissue sections. Alternatively, staining of tissue sections with Alcian blue (AB) or AB in combination with periodic acid–Schiff (PAS) can be used to highlight and count mucus-containing goblet cells.
Transdifferentiation in the airway epithelium is difficult to quantify. In live animals, lineage tracing studies in models of asthma or respiratory infection provided evidence that transdifferentiation occurs (Tyner et al., 2006; Gomperts et al., 2007; Turner et al., 2011). An experienced pathologist may assign a score that reflects the extent of airway remodeling in animal and human lung tissues, but no standard exists, and the results are at best semi-quantitative and study-specific. Some investigators view the appearance of cells bearing morphological characteristics of both ciliated and goblet cells, and co-localization of ciliated and goblet cell markers in situ, as sufficient evidence for transdifferentiation (Gomperts et al., 2007; Rogers, 1994).
Domain of Applicability
There are a number of human studies demonstrating transdifferentiation from ciliated to goblet cells in 3D human airway epithelial models (Gomperts et al., 2007), human bronchial or nasal epithelial cells in vitro (Yoshisue and Hasegawa 2004, Turner et al., 2011, Laoukili et al., 2001) and in COPD patients (Tyner et al., 2006). Transdifferentiation and goblet metaplasia were also shown in mouse respiratory epithelia following IL-13 treatment (Tyner et al., 2006, Fujisawa et al., 2008), although another study found that ciliated cells do not become goblet cells after ovalbumin challenge (Pardo-Saganta et al., 2013). Instillation of IL-13 or sensitization with ovalbumin also resulted in goblet cell metaplasia in rats (Shim et al., 2001; Takeyama et al., 2008). However, to our knowledge, transdifferentiation of ciliated to goblet cells was not directly assessed in these studies.
Casalino-Matsuda, S. M., Monzón, M. E., & Forteza, R. M (2006). Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am J Resp Cell Mol Biol 34, 581-591.
Curran, D.R., and Cohn, L (2010). Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am J Resp Cell Mol Biol 42, 268-275.
Fujisawa, T., Ide, K., 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. Respirology 13, 191-202.
Gomperts, B.N., Kim, L.J., Flaherty, S.A., and Hackett, B.P. (2007). IL-13 regulates cilia loss and foxj1 expression in human airway epithelium. American Journal of Respiratory Cell and Molecular Biology 37, 339-346.
Hays, S.R., and Fahy, J.V. (2006). Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils. Am J Resp Crit Care Med 174, 1018-1024.
Jefferey, P., Rogers, D., Ayers, M., and Shields, P. (1984). Structural aspects of cigarette smoke-induced pulmonary disease. In Smoking and the Lung (Springer), pp. 1-31.
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 Inv 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.
Pardo-Saganta, A., Law, B.M., Gonzalez-Celeiro, M., Vinarsky, V., and Rajagopal, J. (2013). Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge. Am J Resp Cell Mol Biol 48, 364-373.
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.
Rogers, D. (1994). Airway goblet cells: responsive and adaptable front-line defenders. Eur Resp J 7, 1690-1706.
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 Resp Crit Care Med 153, 1412-1418.
Silva, M.A., and Bercik, P. (2012). Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells. Lab Invest 92, 937-948.
Takeyama, K., Tamaoki, J., Kondo, M., Isono, K., and Nagai, A. (2008).Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen. Clin Exp Allergy 38, 857-865.
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.
Tesfaigzi, Y., Harris, J.F., Hotchkiss, J.A., and Harkema, J.R. (2004). DNA synthesis and Bcl-2 expression during development of mucous cell metaplasia in airway epithelium of rats exposed to LPS. Am J Physiol Lung Cell Mol Physiol 286, L268-L274.
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 Resp Cell Mol Biol 44, 276-284.
Tyner, J.W., Kim, E.Y., Ide, K., Pelletier, M.R., Roswit, W.T., Morton, J.D., Battaile, J.T., Patel, A.C., Patterson, G.A., 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.