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Decreased ciliated cell apoptosis leads to Occurrence, Transdifferentiation of ciliated epithelial cells
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Downstream of EGFR activation, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling elicits an anti-apoptotic response in ciliated cells, favoring their survival (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”) (Curran and Cohn, 2010).
Evidence Supporting this KER
There is no direct evidence linking decreased apoptosis in ciliated cells to their transdifferentiation. Co-localization of EGFR and β-tubulin but not CCSP or MUC5AC expression was observed in mouse airways 21 days after inoculation with Sendai virus and in the airways of asthma patients (Tyner et al., 2006; Takeyama et al., 2001). In addition, ciliated cell tagging studies in vitro indicated that the number of ciliated cells decreases following treatment with IL-13, while the number of goblet cells increases (Turner et al., 2011). Together these studies are supportive of transdifferentiation of ciliated into goblet cells.
While the evidence linking decreased apoptosis in ciliated cells to their transdifferentiation is indirect or correlative (Tyner et al., 2006; Silva and Bercik, 2012; Reader et al., 2003; Turner et al., 2011; Ayers et al., 1988; Jefferey et al., 1984), decreased ciliated cell apoptosis following exposure may imply that a (numerically stable) pool of cells is available for IL-13- and/or IL-4-mediated transdifferentiation to goblet cells (Curran and Cohn, 2010). Therefore, our confidence in the biological plausibility of this KER is low.
Uncertainties and Inconsistencies
Experimental evidence in support of this KER 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 rather than transdifferentiation of ciliated cells (Lumsden et al., 1984; Casalino-Matsuda et al., 2006; Hays et al., 2006; Tesfaigzi et al., 2004; Taniguchi et al., 2001).
Treatment of mouse tracheal epithelial cells, differentiated at the air-liquid interface, with IL-13 (100 ng/mL for 5 days) to stimulate goblet cell formation and subsequently with PD153035 (0.3 μM for 3 days) to block EGFR activation did have no significant effect on the rate of apoptosis in Muc5ac-positive cells, whereas the ciliated epithelial cells exhibited significant caspase-positive staining (increased by ca. 10%) (Tyner et al., 2006).
Treatment of mouse tracheal epithelial cells, differentiated at the air-liquid interface, with IL-13 (100 ng/mL for 5 days) to stimulate goblet cell formation gave rise to a transitional cell population. These transitional cells were most prominent early (1–2 days) after initiation of IL-13 treatment, while mature goblet cells without cilia were most abundant at later times (5 days) after treatment. The same observation of transitional cells showing both goblet and ciliated cell marker expression was made in airway epithelial cells cultured from COPD patients and from otherwise healthy lung transplant donors in response to IL-13, within the first day of IL-13 treatment (Tyner et al., 2006).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The studies that support decreased epithelial cell apoptosis resulting in transdifferentiation were performed in mice. Some data from ex vivo lung samples indicate applicability to humans.
Ayers, M., and Jeffery, P. (1988). Proliferation and differentiation in mammalian airway epithelium. Eur. Respir. J. 1, 58-80.
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. 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.
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.
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.
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., Fahy, J., and Nadel, J. (2001). Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am. J. Resp. Crit. Care Med. 163, 511-516.
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.