Upstream eventOccurrence, Transdifferentiation of ciliated epithelial cells
Occurrence, Metaplasia of goblet cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|EGFR Activation Leading to Decreased Lung Function||adjacent||High||Low|
Life Stage Applicability
Key Event Relationship Description
Following injury, airway epithelial repair is accomplished by (transient) remodeling processes. In the absence of cell proliferation, this remodeling is thought to be facilitated by transdifferentiation, i.e. the generation of specialized cell types, such as goblet cells, from other specialized cells, such as ciliated and club cells (Evans et al., 2004; Tesfaigzi, 2006). This transdifferentiation results in what pathologists refer to as goblet cell metaplasia.
Evidence Supporting this KER
Transdifferentiation frequently occurs following airway epithelial injury by inhalation exposures (e.g. cigarette smoke, sulfur 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).
The term metaplasia implies transdifferentiation; metaplasia is defined by the “phenotypic change” or “abnormal transformation of adult, fully differentiated tissue of one kind into a differentiation tissue of another kind” (Harkema and Hotchkiss, 1993; Harkema and Wagner, 2002).
There is no empirical support as the two KEs (transdifferentiation and metaplasia) are equivalent in definition, but represent different levels of biological organization (cellular vs tissue level).
Uncertainties and Inconsistencies
The evidence supporting this KER is indirect or correlative and not in agreement with some 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 at al., 2006; Taniguchi et al., 2011; Hays et al., 2006; Tesfaigzi et al., 2004).
Quantitative Understanding of the Linkage
This KER is difficult to quantify, because the KEs occur on different levels of biological organization and identification of metaplasia is somewhat subjective.
Increased numbers of goblet cells were found following exposure to sulfur dioxide in the periphery of rat lungs, where there are normally none, and this increase is not proportional to the mitotic count (Lamb and Reid, 1968). This suggests that goblet cell numbers are not increasing due to proliferation and could instead result from differentiation of ciliated cells, a process which is referred to as goblet cell metaplasia. Similarly, metaplasia in rat nasal epithelium is associated with low mitotic rates and increased numbers of goblet cells, suggesting that differentiation into goblet cells is occurring rather than goblet cell proliferation (Shimizu et al., 1996; Lamb and Reid, 1968).
The two KEs (transdifferentiation and metaplasia) are equivalent in definition, but represent different levels of biological organization (cellular vs tissue level). As such, there is no empiricial evidence to describe the response-respons relationship.
The timescale for this KER is difficult to evaluate. Studies often study either transdifferentiation in cells or metaplasia in a tissue, but do not provide a temporal analysis of the disappearance of ciliated cells/appearance of goblet cells.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
There are many human studies illustrating transdifferentiation from ciliated to goblet cells or goblet cell metaplasia in 3D airway epithelial models (Gomperts et al., 2007), 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).
Airway epithelial transdifferentiation and goblet metaplasia were also observed in mice (Tyner et al., 2006, Fujisawa et al., 2008) and in rats (Shim et al., 2001; Takeyama et al., 2008). However, to our knowledge, none of these studies measured transdifferentiation of ciliated to goblet cells directly.
Casalino-Matsuda, S.M., Monzón, M.E., and 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 Respir Cell Mol Biol 34, 581-591.
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.
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. Am J Respir Cell Mol Biol 37, 339-346.
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.
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.
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.
Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., Tam, D.C., and Nadel, J.A. (2001). IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am J Physiol Lung Cell Mol Physiol 280, L134–L140.
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.
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.
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.