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Activation, EGFR leads to Occurrence, Transdifferentiation of ciliated epithelial cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|EGFR Activation Leading to Decreased Lung Function||adjacent||Moderate||Moderate||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Airway epithelial injury can be caused by various 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). EGFR was shown to be a key player in this process in both murine and human airway epithelia (Tyner et al., 2006; Hao et al., 2011; Habibovic et al., 2016).
Evidence Supporting this KER
Transdifferentiation was shown to occur following the activation of EGFR-mediated anti-apoptotic signaling in ciliated epithelial cells (Tyner et al., 2006). 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 (Curran & Cohn, 2010).
EGFR can be activated by ROS or IL-13 to lead to ciliated cell transdifferentiation. IL-13 stimulates transdifferentiation of ciliated epithelial cells to goblet cells through EGFR activation increasing MMP/ADAM activity and MAPK activation (Casalino-Matsuda et al., 2006; Yoshisue and Hasegawa, 2004; Tyner et al., 2006).
Two studies showed EGFR involvement in a decrease in goblet cell and increase in ciliated cell numbers or cell-specific marker expression (Yoshisue and Hasegawa, 2004; Casalino-Matsuda et al., 2006). Other studies demonstrated ciliated cell transdifferentiation in response to IL13 in an EGFR-dependent manner in a mouse viral infection model and mouse tracheal epithelial cells in vitro (Tyner et al., 2006), rat nasal epithelial cells (Lee et al., 2000), and human airway epithelial cells (Kim et al., 2002; Hao et al., 2011).
Uncertainties and Inconsistencies
It is not well-known how ciliated cell transdifferentiation occurs in humans. Under normal conditions, lung epithelial cells (except basal cells) are terminally differentiated (Donnelly et al., 1982; Breuer et al., 1990; Rawlins and Hogan, 2008), and which signals initiate the dedifferentiation/redifferentiation process is not well-understood. The available evidence is indirect or correlative. It also is not in agreement with other studies, which showed 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 and goblet cell hyperplasia (Pardo-Sargenta et al., 2013; Hays et al., 2006; Lawson et al., 2002; Tesfaigzi et al., 2004; Taniguchi et al., 2011; Park et al., 2006; Turner et al., 2011).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Two mouse studies demonstrated ciliated cell transdifferentiation and goblet metaplasia in response to virus and/or IL13 (Tyner et al., 2006; Fujisawa et al., 2008). Indirect evidenc is also available from rat studies and studies on human cells and clinical samples.
Breuer, R., Zajicek, G., Christensen, T.G., Lucey, E.C., and Snider, G.L. (1990). Cell Kinetics of Normal Adult Hamster Bronchial Epithelium in the Steady State. Am J Respir Cell Mol Biol 2, 51–58.
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.
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.
Donnelly, G.M., Haack, D.G., and Heird, C.S. (1982). Tracheal epithelium: cell kinetics and differentiation in normal rat tissue. Cell Tissue Kinet 15, 119–130.
Hao, Y., Kuang, Z., Walling, B.E., Bhatia, S., Sivaguru, M., Chen, Y., Gaskins, H.R. and Lau, G.W. (2012). Pseudomonas aeruginosa pyocyanin causes airway goblet cell hyperplasia and metaplasia and mucus hypersecretion by inactivating the transcriptional factor FoxA2. Cell Microbiol 14, 401-415.
Habibovic, A., Hristova, M., Heppner, D.E., Danyal, K., Ather, J.L., Janssen-Heininger, Y.M., Irvin, C.G., Poynter, M.E., Lundblad, L.K., and Dixon, A.E. (2016). DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma. JCI Insight 1.
Hays, S.R., and Fahy, J.V. (2006). Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils. Am J Respir Crit Care Med 174, 1018-1024.
Kim, S., Shim, J., Burgerl, P., Ueki, I., Dao-Pick, T., Tam, D., and Nadel, J. (2002). IL-13-induced Clara cell secretory protein expression in airway epithelium: role of EGFR signaling pathway. Am J Physiol Lung Cell Mol Physiol 283, L67–L75.
Kim, J.H., Lee, S.Y., Bak, S.M., Suh, I.B., Lee, S.Y., Shin, C., Shim, J.J., In, K.H., Kang, K.H., and Yoo, S.H. (2004). Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia. Am J Physiol Lung Cell Mol Physiol 287, L127-L133.
Lawson, G.W., Van Winkle, L.S., Toskala, E., Senior, R.M., Parks, W.C., and Plopper, C.G. (2002). Mouse strain modulates the role of the ciliated cell in acute tracheobronchial airway injury-distal airways. Am J Pathol 160, 315–327.
Lee, H.-M., Takeyama, K., Dabbagh, K., Lausier, J.A., Ueki, I.F., and Nadel, J.A. (2000). Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways. Am J Physiol Lung Cell Mol Physiol 278, L185-L192.
Le Cras, T.D., Acciani, T.H., Mushaben, E.M., Kramer, E.L., Pastura, P.A., Hardie, W.D., Korfhagen, T.R., Sivaprasad, U., Ericksen, M., Gibson, A.M. and Holtzman, M.J., 2010. Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma. Am J Physiol Lung Cell Mol Physiol 300, L414-L421.
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. Respir. Cell Mol. Biol. 48, 364–373.
Park, K.-S., Wells, J.M., Zorn, A.M., Wert, S.E., Laubach, V.E., Fernandez, L.G., and Whitsett, J.A. (2006). Transdifferentiation of ciliated cells during repair of the respiratory epithelium. Am J Respir Cell Mol Biol 34, 151–157.
Rawlins, E.L., and Hogan, B.L.M. (2008). Ciliated epithelial cell lifespan in the mouse trachea and lung. Am J. Physiol Lung Cell Mol Physiol 295, L231–L234.
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 Resp Crit Care Med 153, 1412-1418.
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 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.